OXAZOLIDINONE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS ANTIMYCOBACTERIAL AGENTS

Abstract

A compound of formula (I) and its pharmaceutical^ acceptable salts wherein, A is either hydrogen or fluorine, B is either hydrogen or fluorine, A and B together is hydrogen and fluorine, Ri is a group of formula, wherein, Q is either an alkyl group of two carbon atoms, an alkene group of two carbon atoms or an alkyne group of two carbon atoms Y is oxygen, sulfur or an amino function of formula NR3 wherein, R3 is an alkyl group of 1-4 carbon atoms, both saturated and unsaturated, which can be straight or branched; cycloalkyl of 3-7 carbon atoms; CHO, -COOH, -COOR,; COCR,; CN; aryl or heteroaryl wherein, Rt is an alkyl group of 1-4 carbon atoms, an alkene of 3-6 carbon atoms, an alkyne of 3-6 carbon atoms. Ar is a substituted phenyl ring or a substituted pyridine ring of formula —O-R3 or Ar is a five membered ring of formula 48 or Ar is a fused bicyclic phenyl or pyridine ring of formula wherein, M is either CH or N Z is CH, NH, O, or S, X is a group selected from OR,, NR4R5, N02, SR,, SOOR,, SOONR4R5, F, CI, Br or I, wherein R4 is as defined hereinbefore, and and R3 is as defined hereinbefore R5 is hydrogen or R4 R2 is selected from the groups shown below, and the corresponding N-oxides thereof.

Full Text

F0RM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - OXAZOLIDINONE DERIVATIVES, PROCESS FOR THEIR
PREPARATION AND THEIR USE AS ANTIMYCOBACTERIAL AGENTS
2. Applicants)
(a) NAME : LUPIN LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : 159, C.S.T. Road, Kalina, Santacruz (East),
Mumbai - 400 098, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD OF THE INVENTION
The present invention relates to novel compounds belonging to the class of oxazolidinones useful in the treatment of acid fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp. The present invention further relates to methods for preparation of the novel compounds and to pharmaceutical compositions containing the novel compounds useful in the treatment of tuberculosis. BACKGROUND OF THE INVENTION
Tuberculosis (TB), an infectious disease caused by the bacterium Mycobacterium tuberculosis is transmitted mainly through air, affecting most often the lungs. When persons with pulmonary TB cough they produce tiny droplet nuclei containing M. tuberculosis, which remain suspended in air for a prolonged period of time. A person who breathes the air containing the aforesaid droplet nuclei containing M. tuberculosis can become infected with TB.
TB, one of the three major infectious diseases in the priority list of the World Health Organization's (WHO) agenda kills about two million people around the world every year. About six million new cases are reported every year and nearly 20% of adult deaths and 6% of infant deaths are attributable to the disease (C. Dye et. al., J. Am. Med. Ass., 1999, 282, 677-686). About a billion people are expected to be affected by TB by the year 2020, with 35 million likely to succumb to the disease (WHO Fact Sheet No. 104, Global Alliance for TB Drug Development- Executive Summary of the Scientific Blueprint for TB Development : http://www.who.int/inf-fs/en/factl04.html).
With the emergence of the AIDS epidemic and the increase in cases of HIV coupled with TB as well as the continued resistance of M. tuberculosis to isoniazid and rifampicin, the two most powerful anti-tubercular drugs available today there is an urgent need for new anti-tubercular drugs to combat the killer disease (S. H. E. Kaufmann et. al., Trends Microbiol., 1993, 1,2-5 ; B. R. Bloom et. al., N. Engl. J. Med., 1998, 338, 677-678).
Although, many new compounds are becoming available for fighting a number of infectious diseases, the number of such compounds having antimycobacterial activity are few. This could partly be due to the complexity of research involved and partly due to business considerations (B. N. Roy et. al., J. Ind. Chem. Soc, April 2002, 79, 320-335 and references cited therein).
However, renewed thrust in research in the last decade has resulted in development of new antimycobacterial compounds,
a) differing widely in structures,
b) having different mode/mechanism of action,
c) possessing favourable pharmacokinetic properties,
d) which are safe and have low incidence of side-effects, and
e) which provide a cost-effective dosage regimen.
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Among the aforesaid new compounds, the oxazolidinones first developed during the mid-1980s (W. A. Gregory et. al., J. Med. Chem., 1989, 32,1673-1681 and 1990,33,2569-2578 ; C-H Park et. al., J. Med. Chem., 1992, 35, 1156-1165) are a unique class in themselves. The in vivo results for some of the oxazolidinones show that they are active against various Gram-positive bacteria such as staphylococci, pneumococci and enterococci, including resistant strains such as methicillin-resistant Staphylococcus aureus [MRSA], methicillin-resistant Streptococcus epidermidis [MRSE], penicillin-resistant Streptococcus pneumoniae [PRSP], vancomycin-resistant enterococci [VRE], etc. (B. Riedl et. al., Exp. Opin. Ther. Patents., Ashley Publications Ltd., 1999,9 (5), 625-633 and the references contained therein).
The oxazolidinones inhibit bacterial protein synthesis at a very early step in the initiation of complex formation involved in the process of translating mRNA into protein. The oxazolidinones, in general, are not cross-resistant with any known antibiotic because of this unique mechanism (D. C. Eustice et. al., Antimicrob. Agents Chemother., 1988, 32, 1218 and Biochem. Biophys. Res. Commun., 1988,150. 965).
A feature of the oxazolidinone molecule is that only those compounds, which are enantiomers with a (5S)-acetamidomethyl configuration in the left side of the molecule are known to exhibit antibacterial activity (W. A. Gregory et. al., J. Med. Chem., 1989, 32, 1673-1681). Another feature is that most of such antibacterial compounds invariably carry a (substituted) phenyl ring attached to the nitrogen atom of the oxazolidinone ring in the right side of the molecule (B. Riedl et. al., Exp. Opin. Ther. Patents., Ashley Publications Ltd., 1999, 9 (5), 625-633 and the references contained therein).
The most promising compound among the N-phenyl oxazolidinones, which has been approved for human use is (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidin-yl]methyl]-acetamide), commonly known as linezolid (M. Barbachyn et. al., WO 995/07271). Linezolid possesses good in vitro and in vivo potency against most of the Gram-positive bacteria, including resistant strains {Drugs of the Future, 1996,21.(11), 1116-1123).
The left hand side i. e. position 5- and the right hand side i. e. position 3- respectively of
the oxazolidinone ring nucleus allows for many variations and has resulted in the discovery of a
large number of compounds having antimicrobial and antibacterial properties. Such
representative compounds, albeit not meant to be limiting are disclosed in the following prior art
references. These are:
i) US 4,942,183 (Gregory et. al.) and US 4,948,801 (Carlson et. al.) collectively disclose
certain 3-substituted phenyl- 5-aminomethyl oxazolidinones, possessing useful
antibacterial activity, ii) US 5,529,998 (Habich et. al.) discloses certain 3-benzoxazoyl- and benzothiazolyl-5-
acetyl amino methyl oxazolidinones, useful as antibacterial medicaments.
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iii) US 5,565,571, US 5,654,428, US 5,756,732, US 5,801,246 and US 5,929,248 (Barbachyn et. al.) collectively disclose several substituted aryl and heteroaryl phenyloxazolidinones carrying an acetyl aminomethyl function at the 5-position, specifically oxazolidinones having an aryl or heteroaryl group at the para position of the 3-phenyl ring and additional substituents at the meta positions of the 3-phenyl ring, which are useful as antibacterials.
iv) US 5,652,238 (Brickner et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a hydroxyl acetyl piperazine moiety, active against various Gram-positive bacteria such as staphylococci, pneumococci and enterococci, as well as anerobic organisms such as bacteroides and Clostridia species as well as acid-fast organisms such as Mycobacterium tuberculosis.
v) US 5,684,023 (Riedl et. al.) discloses certain 3- benzofuranyl- and benzothienyl oxazolidinones, carrying an azido, hydroxy or acetyl aminomethyl group at the 5-position, useful as antibacterial medicaments.
vi) US 5,688,792 (Barbachyn et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a (substituted)-morpholine. Such compounds are useful for treatment of microbial infections caused by staphylococci, streptococci, enterococci, Bacteroides spp., Clostridia spp., Mycobacterium tuberculosis, Mycobacterium avium or Mycobacterium spp.
vii) US 5,719,154 (Tucker et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, the said substitution being a pyrimidinyl or pyradazinyl group. Such compounds are useful as antimicrobial agents.
viii) US 5,736,545 (Gadwood et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, the substitution being a five membered heterocycle ring, in particular an azolyl ring. Such compounds are useful in the treatment of microbial infections.
ix) US 5,792,765 (Riedl. et. al.) discloses certain substituted 5-acetyl aminomethyl-3-substituted phenyloxazolidinones, the substitution being a heterocyclic moiety, useful as antibacterial medicaments.
x) US 5,861,413 (Habich et. al.) discloses certain 2-oxo and 2-thio-l,2-dihydroxyqoinolinyl-1-oxazolidinones, useful as antibacterial medicaments.
xi) US 5,880,118 (Barbachyn et. al.) discloses certain substituted 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a
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substituted thiomorholine moiety i. e. oxazine and thiazine derivatives, useful for treatment of microbial infections caused by staphylococci, streptococci, enterococci, Bacteroides spp., Clostridia spp., Mycobacterium tuberculosis, Mycobacterium avium or Mycobacterium spp.
xii) US 5,910,504 and US 6,124,334 (Hutchinson et. al.) collectively disclose certain substituted 5-acetyl aminomethyl-3- phenyloxazolidinones substituted at the para position of the 3-phenyl ring with a heteroaromatic moiety, which is five membered having one to four nitrogen atoms or alternatively, a benzoannulated five-membered heteroaromatic ring having one to four nitrogen atoms, useful as antibacterials.
xiii) US 6,069,160 (Stolle et. al.) discloses certain substituted 5-acetyl aminomethyl-3-benzocyclopentaneoxazolidinones, containing an heteroatom, useful as antibacterial medicaments.
xiv) US 6,227,868 Bl and US 6,410,728 (Sciotti et. al.) collectively disclose certain 5-acetyl aminomethyl-3-phenyloxazolidinones carrying an acetylenic moiety on the 3-phenyl ring, useful for treating bacterial infections, psoriasis, arthritis and toxicity due to chemotherapy.
xv) WO 93/23384 (Hutchinson et. al.) discloses certain substituted 5-acetyl aminomethyl-3 -phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, useful for treatment of microbial infections caused by staphylococci, streptococci, as well as anaerobic organisms such as bacteroides and Clostridia species and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium.
xvi) WO 97/10223 (Gadwood et. al.) discloses certain substituted 5-acetyl aminomethyl-3-aminoaryl oxazolidinone N-oxide compounds, which are exceedingly water soluble and useful in preparation of pharmaceutical compositions for combating a number of human and veterinary pathogens, staphylococci, streptococci, as well as anaerobic organisms such as bacteroides and Clostridia species and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium, Mycobacterium spp. and Mycoplasma spp.
xvii) WO 98/01446 and WO 98/01447 (Betts et. al.) collectively disclose certain substituted 5-acetyl aminomethyl3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, the substitution being a six-membered heteroaryl ring containing two or three ring nitrogen atoms as the only ring heteroatoms, useful as antibacterial agents.
xviii) WO 99/02525 (Thomasco et. al.) discloses certain substituted 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted by a thiadiazolyl or oxadiazolyl moiety, useful as
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antimicrobial agents, effective against a number of human and veterinary pathogens, including Gram-positive and Gram-negative aerobic bacteria.
xix) WO 99/37630 (Gordeev et. al.) discloses oxazolidinone combinatorial libraries, compositionscontaining the same and methods of preparation thereof involving solid phase synthesis, which provides the said compounds for high-throughput screening.
xx) W099/37641 (Bartel. et. al.) discloses certain substituted 5-acetyl aminomethyl-3-bicyclene-substituted oxazolidinones, useful as antibacterial medicaments.
xxi) WO 01/09107 (Gordeev et. al.) discloses certain 3-heteroaryl-5-acetyl aminomethyl oxazolidinones, substituted by a thioacyl, aminocarbonyl, alkoxycarbonyl, aminothiocarbonyl, alkoxythiocarbonyl and alkylthiocarbonyl group, useful in treating or preventing an infectious disorder in humans or animals.
xxii) WO 01/42242 (Paget et. al.) discloses certain substituted 5-acetyl aminomethyl 3-substituted phenyloxazolidinones, the substitution being a bicyclic heterocyclic system, useful as antibacterial agents.
xxiii) WO 02/06278 (Mehta et. al) discloses certain substituted 3-phenyl oxazolidinones and to process for synthesis of the same, the said compounds useful as antibacterial agents, effective against a large number of human and veterinary pathogens, including Gram-positive bacteria and acid fast organisms such as Mycobacterium tuberculosis.
xxiv) WO 02/20515 (Madar et. al.) discloses heterocyclic phenyloxazolidinones, useful for treating bacterial infections. However, only a few of the disclosures described hereinbefore provide compounds that
can be used as antimycobacterials, while most of the others are silent about the antimycobacterial
activity of the disclosed compounds.
A need, therefore, exists for new compounds possessing potent antimycobacterial
properties for treatment of TB, which as mentioned hereinearlier is assuming alarming
proportions.
OBJECTS OF THE INVENTION
It is thus the basic object of the present invention to synthesize, identify and provide new
compounds belonging to the class of oxazolidinones, possessing potent antimycobacterial
properties especially for treatment of acid fast organisms such as Mycobacterium tuberculosis,
Mycobacterium avium-intracellular complex, M. fortuitum and M. kansai.
Another object is directed to providing antimycobacterial pharmaceutical composition
effective in inhibiting/treating the generation of mycobacterial conditions/cells including
Mycotacterium tuberculosis, drug resistant Mycobacterium tuberculosis, Mycobacterium avium-intracellular complex, M fortuitum and Mkansai.
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Yet another object is directed to providing a method of treating/inhibiting mycobacterial cells/conditions involving the administrations of effective amount of the novel antimycobacterial compound and/or its salts /composition of the invention. SUMMARY OF THE INVENTION
Thus according to the basic aspect of the present invention there is provided compound of formula (I) and its pharmaceutically acceptable salts thereof

R is an alkane of 1-4 carbon atoms, an alkene of 3-6 carbon atoms, an alkyne of 3-6 carbon
atoms, and
Ar is an aromatic carbocycle represented by

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wherein,
X is OR4, NR4R5, N02, SR4, SOOR4, SOONR4R5, Br, CI, F, or I,
M is-CHorN,and
Zis-CH,-NH,OorS
and wherein,
R3 and R4 are as described hereinbefore, and
R5 is H, or same as R4, and
R.2 is selected from the groups shown below, and the corressponding N-oxides thereof

Heteroaryl or Heterocycloalkyl wherein K is O, S, SO, S02, or CH2
According to another aspect of the invention there is provided a pharmaceutical
composition comprising:
i) atleast one of an antimycobacterially effective amounts of compound of formula I and
pharmaceutically acceptable salts there of; and ii) a pharmaceutically acceptable carrier.
According to yet another aspect of the present invention there is provided a method of inhibiting growth of mycobacterial cells such as Mycobacterium tuberculosis, drug resistant Mycobacterium tuberculosis, Mycobacterium avium-intracellular complex, M. fortuitum and M.kansai.,comprising administering an antimycobacterially effective amount of the compound of formula I and/or pharmaceutically acceptable salts thereof.
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According to yet another aspect of the present invention there is provided a method of treating mycobacterial conditions such as Mycobacterium tuberculosis, drug resistant Mycobacterium tuberculosis, Mycobacterium avium-intracellular complex, M. fortuitum and M kansai, comprising administering an antimycobacterially effective amount of the compound of formula I and/or pharmaceutically acceptable salts thereof.
According to another aspect, there is provided a process for the manufacture of the compound of formula I or its pharmaceutically acceptable salts comprising : coupling the amino fragments of compound of formula II with the carboxylic acid fragment of formula III.
The above disclosed compound of formula I its pharmaceutically acceptable salts thereof are found to have antimycobacterial properties and the same in admixture with pharmaceutically active additives, an be administrated orally or paranterally for treatement of mycobacterial conditions especially TB. DETAILED DESCRIPTION OF THE INVENTION
In the pharmaceutically active compound of formula (I) of this invention,

the definition of the symbols and groups A, B, Rt and R2 are as follows :
A is either hydrogen or fluorine,
B is either hydrogen or fluorine,
A and B together is hydrogen and fluorine,
When A is hydrogen, B is fluorine and vice-versa.
R1 represents a group of formula,

Q is either an alkyl group of two carbon atoms (CH2-CH2), an alkene group of two to carbon atoms (CH=CH), or an alkyne group of two carbon atoms (C=C)
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Y can either be oxygen, sulfur or an amino function of formula NR3, wherein
R3 is an alkyl group of 1-4 carbon atoms, both saturated and unsaturated, which can be straight or
branched. Suitable alkyl groups are methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl, tert-
butyl, ethylene, propylene, 1, butene, both the geometric isomers of 2-butene i. e.(cis)-2-butene
and (trans)-2-butene, and iso-butylene. or
R3 is a cycloalkyl group of 3-7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl, or
R3 is a carboxylic acid group (-COOH) or a carboxylic acid ester of formula-COOR4, wherein
R4 is H, an alkyl group of 1-4 carbon atoms, an alkene of 3-6 carbon atoms, an alkyne of 3-6
carbon atoms.
R3 is further an aldehyde (-CHO), an acetyl group (-COCR4), wherein R4 is as mentioned
hereinbefore or R3 is a nitrile (CN), aryl or heteroaryl, wherein
Aryl is phenyl substituted with (0) or (1) of-F, -CI, -OCH3, -OH, -NH2, -CrC4 alkyl, -O-C(O)-
OCH3,-N02or-CN,and
Heteroaryl
or Ar is a five membered ring of formula
or Ar is a fused bicyclic phenyl or pyridine ring of formula
10
The group Ar is a substituted phenyl ring or a substituted pyridine ring of formula

wherein,
M is either CH or N; Z is -CH, -NH, O or S and R3 is as defined hereinbefore,
X is a group selected from OR4, NR4R5, N02, SR4, SOOR4, SOONR4R5, F, CI, Br or I, wherein
R4 is as defined hereinbefore, and
R5 is hydrogen or R4.
R2 is selected from the groups shown below, and the corresponding N-oxides thereof.

78. (S) - N -[ [ 3 - ( 3 - fluoro - 4 - thiomorpholinylphenyl ) - 2 — oxo - 5 - oxazolidinyl ] methyl ] - 4 - ( 2,4 - dimethyl- 4 ethylphenyl) - 4 - oxobutanamide.
The respective N-oxides of the group R2 of the compounds of formula I listed above also form a novel aspect of the present invention.
The pharmaceutically active compounds of formula (I), the corresponding N-oxides of the group R2 and pharmaceutically acceptable salts thereof of this invention can be prepared by methods known to one skilled in the art.
Typically, compounds of formula (I), can be prepared by coupling of the amino fragment of formula (II)

Scheme-!
General method for synthesis of compounds of formula (I)

In a typical experiment, the amine compound of formula (II), wherein the groups A, B, and R2 have the same meanings as defined hereinbefore is dissolved in a 1:1 mixture of tertahydrofuran and water or a 1:1 mixture of methylene chloride and water. To the solution is added the carboxylic acid compound of formula (III), followed by addition of 1-hydroxybenztriazole (HOBt). The resulting mixture is cooled to a temperature of 0-5° C to which l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.1 Eq.) is added and gradually allowed to warm to room temperature and agitated at this temperature for 24 hours. At the end of
17

In a typical method, morpholine, thiomorpholine, piperidine, 4-benzyl piperazine, pyrrolidine, 1,2,4-triazine, 12,3-benzotriazine, benzyl amine, a heterocycloalkyl or a heteroaryl moiety etc., each one of which corresponds to the group R2 defined hereinbefore is reacted with 3,4-difluoro nitrobenzene in the presence of a base and a solvent to give the corresponding derivative in which the fluorine atom at 4-position is substituted by the group R2. The nitro group in the compound thus obtained is reduced to amino group, which is thereafter protected by a suitable protective group. Reaction of the N-protected compound thus obtained with (R)-glycidyl butyrate in the presence of a strong base like n-butyl lithium leads to formation of the 5-hydroxymethyl oxazolidinone ring. The hydroxy group in the compound thus obtained is converted to sulfonyl derivative, for e.g. a methanesulfonyloxy (mesyl) or a p-toluenesulfonyloxy (tosyl) derivative by reaction with methanesulfonyl chloride or p-toluenesulfonyl chloride respectively. Reaction of the respective mesyl or tosyl derivative with sodium azide gives the corresponding azide, which is converted to the amine compound of formula (II) by standard methods, for e.g. by reaction with a triaryl/trialkyl phosphine, followed by hydrolysis.
The starting carboxylic acid fragments of formula (III), wherein the group Ar has the same meaning as defined hereinearlier are prepared as per the method disclosed in Org. Reactions, 1949, 5, 229-289; Quart. Rev. Chem. Soc, 1954, 8, 355-379; Chem. Rev., 1955, 55, 229-281, and J. Am. Chem. Soc, 1947, 69, 1784-1786. The method is essentially summarized in Scheme-HI.
Scheme-Ill General method for synthesis ofalkane and alkene carboxylic acid s of formula (HI)

In a typical method, the aromatic compound Ar-H, wherein Ar is as defined hereinbefore is reacted with succinic anhydride in the presence of a Lewis acid, such as anhydrous aluminium chloride and in the presence of an anhydrous solvent and the mixture heated to 100° C to give the carboxylic acid derivatives of formula (HI), wherein Q is alkyl of 1-4 carbon atoms.
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Similarly, compounds of formula (III), wherein Q is an alkene (CH=CH) are prepared by reaction of the aromatic compound Ar-H, wherein Ar is as defined hereinbefore with maleic anhydride under the same conditions mentioned hereinbefore.
Compounds of formula (III), wherein Q is an alkyne (C=C) are prepared by reaction of propiolic acid ester with an aldehyde of formula Ar-CHO in the presence of butyl lithium and in the presence of an aprotic solvent such as THF at -78° C to give the corresponding secondary alcohol, which is oxidized to the keto derivative using manganese dioxide as the oxidizing agent. Saponification gives the carboxylic acid derivative of formula (ID) [ US 4,929,741 (A. Fischili et. al.) ] The synthesis is summarized in Scheme-IV.

against M. tuberculosis including sensitive and resistant strains are summarized in Table-I. The MIC value of a representative preferred Compound No. 30 of formula I against different species of mycobacteria is summarized in Table-II. in vitro Growth Inhibition assay
The ability of the compounds 1-78 of formula (I) of this invention to inhibit the growth of Mycobacterium species was determined by the BACTEC 460 TB system. The reference strain M tuberculosis H37Rv ATCC 27294 was grown in Middlebrook 7H9 broth containing 10% ADC
supplement at 37°C on a rotay shaker at 150 rpm for grown for 7days. The turbidity of the culture was adjusted to 1.0 Mc farland. The BACTEC 7H12B medium vials were seeded with 0.1ml of the 1.0 Mc farland adjusted M. tuberculosis culture. In the control vials 0.1ml of the culture was added after lOOfold dilution of the initial inoculum. Stock solution of lmg/ml of each compound was prepared in DMSO in separate sterile tubes. The compounds were further diluted to concentration of 25 ^g/100 ul, 0.1ml was than added to the 7H12B vial containing mycobacterial culture so that final concentration of the compound 6.25 u.g/ml. The cap in all the vials were cleaned with isopropanyl alcohol and kept in racks. The vials were then incubated at 37°C without shaking. Test vials was read daily on the BACTEC system till the GI of the control vial reached > 30.Once the GI in the control reached 30 AGI (GI = GI (n> - GI („.i) ) was determined for all test and control vials. If AGI of test vial is less than that of the control vial the culture was sensitive to the test compound. in vitro Agar Dilution assay
MIC of compound of formula (I) of this invention against strains of Mycobacterium were determined by a reference agar dilution method as per the NCCLS- M24-T2. recommendations. The compounds were dissolved in DMSO and diluted twofold to obtain ten serial dilutions of each compound. Appropriate volume of compounds were incorporated into duplicate plates of Middlebrook7H10 agar medium supplemented with 10% Middlebrook supplement oleic acid-albumin-dextrose (OADC) enrichment at concentration of 0.03u,g/ml to 16|j,g/ml. Test organisms (mycobacterium strains) were grown in Middle brook 7H9 broth containing 0.05% Tween-80 and 10% ADC supplement. After 7 days of incubation at 37°C the broths were adjusted to the turbidity of 1.0 McFarland standard; the organism were further diluted 10 fold in sterile water containing 0.10% Tween-80. The resulting mycobacterial suspensions were spotted (3-5jxl/spot) onto drug supplemented 7H10 media plates. The plates were sealed and incubated at 37°Cfor 3-4 weeks in upright position. The MIC was recorded as the lowest dilution of the drug that completely inhibited the growth of test organisms. Test isolates included 10 clinical isolates that were generally susceptible to common tubercular agents and 10 strains that were resistant to one or more standard anti tubercular drugs. Appropriate reference strains and control drug was included in each batch of test.
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in vivo studies:
The efficacy of the compound of formula (I) of this invention was also evaluated in murine model of pulmonary tuberculosis. Mycobacterium tuberculosis cultures grown in Middle brook 7H9 broth containing 0.05% Tween-80 and 10% ADC supplement at 37°C for 7 days on a rotary shaker. For, animal inoculation liquid cultures were declumped by brief sonication and were diluted appropriately in 7H9 broth to obtain a concentration of lxl07CFU's/ 0.2ml. Four-week-old male outbred Swiss albino mice housed in a pathogen free, biosafety level 3 environment within micro isolator cages were used throughout the study. Infections were produced by intravenous inoculation into caudal tail vein of 0.2ml of declumped M. tuberculosis suspension. Following infection, mice were randomly distributed in different groups of six each.
Treatment for initial study was started one day after infection. For, treatment Compound No. 30 of formula I was dissolved in 10% PEG. Isoniazid was dissolved in sterile water. The drugs were prepared each morning prior to administration. Therapy was given 5 days per week for four weeks. All the agents were administered by gavage and were dosed at 50,25,12.5mg / kg of body weight. Control group of infected but untreated mice were killed at the initiation of therapy (early control) or at the end of the treatment period (late control). Mice were sacrificed by cervical dislocation 3-5 days after the administration of the last dose of drug. The spleens and right lung were removed aseptically and homogenized in tissue homogeniser. At least 4 serial tenfold dilution of the homogenate was plated onto selective Middlebrook 7H11 agar plates in duplicate. The colony counts were recorded after incubation at 37°C for 4 weeks. The viable cell counts were converted to Logio values. A compound showing 2 Log reduction in viable counts compared to the controls was considered significant.
The in vivo data for a representative compound of formula (I) is given in Table-II.
Acute toxicity of Compound No. 30 of Chart-I was estimated in mice and the LDo was found to be >1000 mg/kg P. O.
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Lung Spleen Lung Spleen
1 Compound 30 of Chart-I
50mg/kg 25mg/kg 12.5mg/kg 2.12 2.21 4.34 2.09 2.13 4.30 2.40 2.30 0.20 2.53 2.49 0.26
2 Isoniazid
50mg/kg 25mg/kg 12.5mg/kg 2.03 2.11 2.95 1.92 2.11 2.94 2.49 2.41 1.57 2.70 2.51 1.68
3 Infected early control 4.52 4.62
4 Infected late control 6.57 6.37
a- inoculation of logio:- 7.00 Mycobacteria.
b- mice were dosed 5 day/week for 4 weeks. From day 1 -28.
c- difference in mean logio number CFU from that of early controls.
The compound of formula I of this invention may be administrated to a subject such as a human being or an animal in need of such an administration through any route appropriate to the condition to be treatede. Suitable routes of administration include oral, rectal, nasal, topical (both buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intradermal, intrathecal and epidural).
Pharmaceutical compositions of compound of formula I can be prepared in adjunction with inert pharmaceutically acceptable carriers, which can either be solid or liquid.
Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories and ointments. The solid carriers can be one or more substances which may act also as diluents, flavouring agents, solubilisers, lubricants, suspending agents, binders or tablet disintegrating agents. It can also be finely divided solid which is in admixture with finely divided active compound. Suitable solid carriers are lactose, pectin, dicalcium phosphate, microcrystalline cellulose, sucrose, kaolin, dextrin, gelatin, starch, tragacanth, low melting wax, coca butter and the like.
Liquid preparations include solutions, suspensions and emulsions, e.g. solutions of compound of formula I in water or water-propylene glycol mixture for parenteral injection. Liquid preparations can also be formulated along with non-ionic surfactants and edible oils such as corn, peanut and sesame oils. Aqueous solutions for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours stabilizing and thickening
46

agents, as required. Aqueous suspension for oral use can be made by dispersing the finely divided active component in water with a viscous material, e.g. natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose and othe known suspending agents. The adjuvants may also include preserving agents and anti-oxidants.
Compositions for topical application may take the form of liquids or gels, containing a therapeutically effective concentration of compound of formula I admixed with a dermatologically acceptable carrier.
The pharmaceutical preparations may be in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage can be in the form of tablets, capsules, powdersin vials or ampoules, ointments, gels, creams or any other form. The quantity or concentration of the active compound in such unit dose preparations may be varied or adjusted according to the particular application and potency of the active ingredient.
47

A compound of formula (I) and its pharmaceutical^ acceptable salts

wherein,
A is either hydrogen or fluorine,
B is either hydrogen or fluorine,
A and B together is hydrogen and fluorine,
Ri is a group of formula,

wherein,
Q is either an alkyl group of two carbon atoms, an alkene group of two carbon atoms or
an alkyne group of two carbon atoms
Y is oxygen, sulfur or an amino function of formula NR3
wherein,
R3 is an alkyl group of 1-4 carbon atoms, both saturated and unsaturated, which can be
straight or branched; cycloalkyl of 3-7 carbon atoms; CHO, -COOH, -COOR,; COCR,;
CN; aryl or heteroaryl
wherein,
Rt is an alkyl group of 1-4 carbon atoms, an alkene of 3-6 carbon atoms, an alkyne of
3-6 carbon atoms.
Ar is a substituted phenyl ring or a substituted pyridine ring of formula

—O-R3
or Ar is a five membered ring of formula
48

or Ar is a fused bicyclic phenyl or pyridine ring of formula

wherein,
M is either CH or N
Z is CH, NH, O, or S,
X is a group selected from OR,, NR4R5, N02, SR,, SOOR,, SOONR4R5, F, CI, Br or I,
wherein R4 is as defined hereinbefore, and
and R3 is as defined hereinbefore
R5 is hydrogen or R4
R2 is selected from the groups shown below, and the corresponding N-oxides thereof.

A compound according to Claim 1 wherein in said compound of formula I Aryl is phenyl substituted with (0) or (1) of F, CI, "OCH3, "OH, "NH2, CrC4 alkyl, 0-C(0)-OCH3," N02or"CN.
49

FIELD OF THE INVENTION
The present invention relates to novel compounds belonging to the class of oxazolidinones useful in the treatment of acid fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp. The present invention further relates to methods for preparation of the novel compounds and to pharmaceutical compositions containing the novel compounds useful in the treatment of tuberculosis. BACKGROUND OF THE INVENTION
Tuberculosis (TB), an infectious disease caused by the bacterium Mycobacterium tuberculosis is transmitted mainly through air, affecting most often the lungs. When persons with pulmonary TB cough they produce tiny droplet nuclei containing M. tuberculosis, which remain suspended in air for a prolonged period of time. A person who breathes the air containing the aforesaid droplet nuclei containing M. tuberculosis can become infected with TB.
TB, one of the three major infectious diseases in the priority list of the World Health Organization's (WHO) agenda kills about two million people around the world every year. About six million new cases are reported every year and nearly 20% of adult deaths and 6% of infant deaths are attributable to the disease (C. Dye et. al., J. Am. Med. Ass., 1999, 282, 677-686). About a billion people are expected to be affected by TB by the year 2020, with 35 million likely to succumb to the disease (WHO Fact Sheet No. 104, Global Alliance for TB Drug Development- Executive Summary of the Scientific Blueprint for TB Development : http://www.who.int/inf-fs/en/factl04.html).
With the emergence of the AIDS epidemic and the increase in cases of HIV coupled with TB as well as the continued resistance of M. tuberculosis to isoniazid and rifampicin, the two most powerful anti-tubercular drugs available today there is an urgent need for new anti-tubercular drugs to combat the killer disease (S. H. E. Kaufmann et. al., Trends Microbiol., 1993, 1,2-5 ; B. R. Bloom et. al., N. Engl. J. Med., 1998, 338, 677-678).
Although, many new compounds are becoming available for fighting a number of infectious diseases, the number of such compounds having antimycobacterial activity are few. This could partly be due to the complexity of research involved and partly due to business considerations (B. N. Roy et. al., J. Ind. Chem. Soc, April 2002, 79, 320-335 and references cited therein).
However, renewed thrust in research in the last decade has resulted in development of new antimycobacterial compounds,
a) differing widely in structures,
b) having different mode/mechanism of action,
c) possessing favourable pharmacokinetic properties,
d) which are safe and have low incidence of side-effects, and
e) which provide a cost-effective dosage regimen.
2

Among the aforesaid new compounds, the oxazolidinones first developed during the mid-1980s (W. A. Gregory et. al., J. Med. Chem., 1989, 32,1673-1681 and 1990,33,2569-2578 ; C-H Park et. al., J. Med. Chem., 1992, 35, 1156-1165) are a unique class in themselves. The in vivo results for some of the oxazolidinones show that they are active against various Gram-positive bacteria such as staphylococci, pneumococci and enterococci, including resistant strains such as methicillin-resistant Staphylococcus aureus [MRSA], methicillin-resistant Streptococcus epidermidis [MRSE], penicillin-resistant Streptococcus pneumoniae [PRSP], vancomycin-resistant enterococci [VRE], etc. (B. Riedl et. al., Exp. Opin. Ther. Patents., Ashley Publications Ltd., 1999,9 (5), 625-633 and the references contained therein).
The oxazolidinones inhibit bacterial protein synthesis at a very early step in the initiation of complex formation involved in the process of translating mRNA into protein. The oxazolidinones, in general, are not cross-resistant with any known antibiotic because of this unique mechanism (D. C. Eustice et. al., Antimicrob. Agents Chemother., 1988, 32, 1218 and Biochem. Biophys. Res. Commun., 1988,150. 965).
A feature of the oxazolidinone molecule is that only those compounds, which are enantiomers with a (5S)-acetamidomethyl configuration in the left side of the molecule are known to exhibit antibacterial activity (W. A. Gregory et. al., J. Med. Chem., 1989, 32, 1673-1681). Another feature is that most of such antibacterial compounds invariably carry a (substituted) phenyl ring attached to the nitrogen atom of the oxazolidinone ring in the right side of the molecule (B. Riedl et. al., Exp. Opin. Ther. Patents., Ashley Publications Ltd., 1999, 9 (5), 625-633 and the references contained therein).
The most promising compound among the N-phenyl oxazolidinones, which has been approved for human use is (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidin-yl]methyl]-acetamide), commonly known as linezolid (M. Barbachyn et. al., WO 995/07271). Linezolid possesses good in vitro and in vivo potency against most of the Gram-positive bacteria, including resistant strains {Drugs of the Future, 1996,21.(11), 1116-1123).
The left hand side i. e. position 5- and the right hand side i. e. position 3- respectively of
the oxazolidinone ring nucleus allows for many variations and has resulted in the discovery of a
large number of compounds having antimicrobial and antibacterial properties. Such
representative compounds, albeit not meant to be limiting are disclosed in the following prior art
references. These are:
i) US 4,942,183 (Gregory et. al.) and US 4,948,801 (Carlson et. al.) collectively disclose
certain 3-substituted phenyl- 5-aminomethyl oxazolidinones, possessing useful
antibacterial activity, ii) US 5,529,998 (Habich et. al.) discloses certain 3-benzoxazoyl- and benzothiazolyl-5-
acetyl amino methyl oxazolidinones, useful as antibacterial medicaments.
3

iii) US 5,565,571, US 5,654,428, US 5,756,732, US 5,801,246 and US 5,929,248 (Barbachyn et. al.) collectively disclose several substituted aryl and heteroaryl phenyloxazolidinones carrying an acetyl aminomethyl function at the 5-position, specifically oxazolidinones having an aryl or heteroaryl group at the para position of the 3-phenyl ring and additional substituents at the meta positions of the 3-phenyl ring, which are useful as antibacterials.
iv) US 5,652,238 (Brickner et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a hydroxyl acetyl piperazine moiety, active against various Gram-positive bacteria such as staphylococci, pneumococci and enterococci, as well as anerobic organisms such as bacteroides and Clostridia species as well as acid-fast organisms such as Mycobacterium tuberculosis.
v) US 5,684,023 (Riedl et. al.) discloses certain 3- benzofuranyl- and benzothienyl oxazolidinones, carrying an azido, hydroxy or acetyl aminomethyl group at the 5-position, useful as antibacterial medicaments.
vi) US 5,688,792 (Barbachyn et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a (substituted)-morpholine. Such compounds are useful for treatment of microbial infections caused by staphylococci, streptococci, enterococci, Bacteroides spp., Clostridia spp., Mycobacterium tuberculosis, Mycobacterium avium or Mycobacterium spp.
vii) US 5,719,154 (Tucker et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, the said substitution being a pyrimidinyl or pyradazinyl group. Such compounds are useful as antimicrobial agents.
viii) US 5,736,545 (Gadwood et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, the substitution being a five membered heterocycle ring, in particular an azolyl ring. Such compounds are useful in the treatment of microbial infections.
ix) US 5,792,765 (Riedl. et. al.) discloses certain substituted 5-acetyl aminomethyl-3-substituted phenyloxazolidinones, the substitution being a heterocyclic moiety, useful as antibacterial medicaments.
x) US 5,861,413 (Habich et. al.) discloses certain 2-oxo and 2-thio-l,2-dihydroxyqoinolinyl-1-oxazolidinones, useful as antibacterial medicaments.
xi) US 5,880,118 (Barbachyn et. al.) discloses certain substituted 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a
4

substituted thiomorholine moiety i. e. oxazine and thiazine derivatives, useful for treatment of microbial infections caused by staphylococci, streptococci, enterococci, Bacteroides spp., Clostridia spp., Mycobacterium tuberculosis, Mycobacterium avium or Mycobacterium spp.
xii) US 5,910,504 and US 6,124,334 (Hutchinson et. al.) collectively disclose certain substituted 5-acetyl aminomethyl-3- phenyloxazolidinones substituted at the para position of the 3-phenyl ring with a heteroaromatic moiety, which is five membered having one to four nitrogen atoms or alternatively, a benzoannulated five-membered heteroaromatic ring having one to four nitrogen atoms, useful as antibacterials.
xiii) US 6,069,160 (Stolle et. al.) discloses certain substituted 5-acetyl aminomethyl-3-benzocyclopentaneoxazolidinones, containing an heteroatom, useful as antibacterial medicaments.
xiv) US 6,227,868 Bl and US 6,410,728 (Sciotti et. al.) collectively disclose certain 5-acetyl aminomethyl-3-phenyloxazolidinones carrying an acetylenic moiety on the 3-phenyl ring, useful for treating bacterial infections, psoriasis, arthritis and toxicity due to chemotherapy.
xv) WO 93/23384 (Hutchinson et. al.) discloses certain substituted 5-acetyl aminomethyl-3 -phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, useful for treatment of microbial infections caused by staphylococci, streptococci, as well as anaerobic organisms such as bacteroides and Clostridia species and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium.
xvi) WO 97/10223 (Gadwood et. al.) discloses certain substituted 5-acetyl aminomethyl-3-aminoaryl oxazolidinone N-oxide compounds, which are exceedingly water soluble and useful in preparation of pharmaceutical compositions for combating a number of human and veterinary pathogens, staphylococci, streptococci, as well as anaerobic organisms such as bacteroides and Clostridia species and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium, Mycobacterium spp. and Mycoplasma spp.
xvii) WO 98/01446 and WO 98/01447 (Betts et. al.) collectively disclose certain substituted 5-acetyl aminomethyl3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, the substitution being a six-membered heteroaryl ring containing two or three ring nitrogen atoms as the only ring heteroatoms, useful as antibacterial agents.
xviii) WO 99/02525 (Thomasco et. al.) discloses certain substituted 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted by a thiadiazolyl or oxadiazolyl moiety, useful as
5

antimicrobial agents, effective against a number of human and veterinary pathogens, including Gram-positive and Gram-negative aerobic bacteria.
xix) WO 99/37630 (Gordeev et. al.) discloses oxazolidinone combinatorial libraries, compositionscontaining the same and methods of preparation thereof involving solid phase synthesis, which provides the said compounds for high-throughput screening.
xx) W099/37641 (Bartel. et. al.) discloses certain substituted 5-acetyl aminomethyl-3-bicyclene-substituted oxazolidinones, useful as antibacterial medicaments.
xxi) WO 01/09107 (Gordeev et. al.) discloses certain 3-heteroaryl-5-acetyl aminomethyl oxazolidinones, substituted by a thioacyl, aminocarbonyl, alkoxycarbonyl, aminothiocarbonyl, alkoxythiocarbonyl and alkylthiocarbonyl group, useful in treating or preventing an infectious disorder in humans or animals.
xxii) WO 01/42242 (Paget et. al.) discloses certain substituted 5-acetyl aminomethyl 3-substituted phenyloxazolidinones, the substitution being a bicyclic heterocyclic system, useful as antibacterial agents.
xxiii) WO 02/06278 (Mehta et. al) discloses certain substituted 3-phenyl oxazolidinones and to process for synthesis of the same, the said compounds useful as antibacterial agents, effective against a large number of human and veterinary pathogens, including Gram-positive bacteria and acid fast organisms such as Mycobacterium tuberculosis.
xxiv) WO 02/20515 (Madar et. al.) discloses heterocyclic phenyloxazolidinones, useful for treating bacterial infections. However, only a few of the disclosures described hereinbefore provide compounds that
can be used as antimycobacterials, while most of the others are silent about the antimycobacterial
activity of the disclosed compounds.
A need, therefore, exists for new compounds possessing potent antimycobacterial
properties for treatment of TB, which as mentioned hereinearlier is assuming alarming
proportions.
OBJECTS OF THE INVENTION
It is thus the basic object of the present invention to synthesize, identify and provide new
compounds belonging to the class of oxazolidinones, possessing potent antimycobacterial
properties especially for treatment of acid fast organisms such as Mycobacterium tuberculosis,
Mycobacterium avium-intracellular complex, M. fortuitum and M. kansai.
Another object is directed to providing antimycobacterial pharmaceutical composition
effective in inhibiting/treating the generation of mycobacterial conditions/cells including
Mycotacterium tuberculosis, drug resistant Mycobacterium tuberculosis, Mycobacterium avium-intracellular complex, M fortuitum and Mkansai.
6

Yet another object is directed to providing a method of treating/inhibiting mycobacterial cells/conditions involving the administrations of effective amount of the novel antimycobacterial compound and/or its salts /composition of the invention. SUMMARY OF THE INVENTION
Thus according to the basic aspect of the present invention there is provided compound of formula (I) and its pharmaceutically acceptable salts thereof

R is an alkane of 1-4 carbon atoms, an alkene of 3-6 carbon atoms, an alkyne of 3-6 carbon
atoms, and
Ar is an aromatic carbocycle represented by

7

wherein,
X is OR4, NR4R5, N02, SR4, SOOR4, SOONR4R5, Br, CI, F, or I,
M is-CHorN,and
Zis-CH,-NH,OorS
and wherein,
R3 and R4 are as described hereinbefore, and
R5 is H, or same as R4, and
R.2 is selected from the groups shown below, and the corressponding N-oxides thereof

Heteroaryl or Heterocycloalkyl wherein K is O, S, SO, S02, or CH2
According to another aspect of the invention there is provided a pharmaceutical
composition comprising:
i) atleast one of an antimycobacterially effective amounts of compound of formula I and
pharmaceutically acceptable salts there of; and ii) a pharmaceutically acceptable carrier.
According to yet another aspect of the present invention there is provided a method of inhibiting growth of mycobacterial cells such as Mycobacterium tuberculosis, drug resistant Mycobacterium tuberculosis, Mycobacterium avium-intracellular complex, M. fortuitum and M.kansai.,comprising administering an antimycobacterially effective amount of the compound of formula I and/or pharmaceutically acceptable salts thereof.
8

According to yet another aspect of the present invention there is provided a method of treating mycobacterial conditions such as Mycobacterium tuberculosis, drug resistant Mycobacterium tuberculosis, Mycobacterium avium-intracellular complex, M. fortuitum and M kansai, comprising administering an antimycobacterially effective amount of the compound of formula I and/or pharmaceutically acceptable salts thereof.
According to another aspect, there is provided a process for the manufacture of the compound of formula I or its pharmaceutically acceptable salts comprising : coupling the amino fragments of compound of formula II with the carboxylic acid fragment of formula III.
The above disclosed compound of formula I its pharmaceutically acceptable salts thereof are found to have antimycobacterial properties and the same in admixture with pharmaceutically active additives, an be administrated orally or paranterally for treatement of mycobacterial conditions especially TB. DETAILED DESCRIPTION OF THE INVENTION
In the pharmaceutically active compound of formula (I) of this invention,

the definition of the symbols and groups A, B, Rt and R2 are as follows :
A is either hydrogen or fluorine,
B is either hydrogen or fluorine,
A and B together is hydrogen and fluorine,
When A is hydrogen, B is fluorine and vice-versa.
R1 represents a group of formula,

Q is either an alkyl group of two carbon atoms (CH2-CH2), an alkene group of two to carbon atoms (CH=CH), or an alkyne group of two carbon atoms (C=C)
9

Y can either be oxygen, sulfur or an amino function of formula NR3, wherein
R3 is an alkyl group of 1-4 carbon atoms, both saturated and unsaturated, which can be straight or
branched. Suitable alkyl groups are methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl, tert-
butyl, ethylene, propylene, 1, butene, both the geometric isomers of 2-butene i. e.(cis)-2-butene
and (trans)-2-butene, and iso-butylene. or
R3 is a cycloalkyl group of 3-7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl, or
R3 is a carboxylic acid group (-COOH) or a carboxylic acid ester of formula-COOR4, wherein
R4 is H, an alkyl group of 1-4 carbon atoms, an alkene of 3-6 carbon atoms, an alkyne of 3-6
carbon atoms.
R3 is further an aldehyde (-CHO), an acetyl group (-COCR4), wherein R4 is as mentioned
hereinbefore or R3 is a nitrile (CN), aryl or heteroaryl, wherein
Aryl is phenyl substituted with (0) or (1) of-F, -CI, -OCH3, -OH, -NH2, -CrC4 alkyl, -O-C(O)-
OCH3,-N02or-CN,and
Heteroaryl
or Ar is a five membered ring of formula
or Ar is a fused bicyclic phenyl or pyridine ring of formula
10
The group Ar is a substituted phenyl ring or a substituted pyridine ring of formula

wherein,
M is either CH or N; Z is -CH, -NH, O or S and R3 is as defined hereinbefore,
X is a group selected from OR4, NR4R5, N02, SR4, SOOR4, SOONR4R5, F, CI, Br or I, wherein
R4 is as defined hereinbefore, and
R5 is hydrogen or R4.
R2 is selected from the groups shown below, and the corresponding N-oxides thereof.

78. (S) - N -[ [ 3 - ( 3 - fluoro - 4 - thiomorpholinylphenyl ) - 2 — oxo - 5 - oxazolidinyl ] methyl ] - 4 - ( 2,4 - dimethyl- 4 ethylphenyl) - 4 - oxobutanamide.
The respective N-oxides of the group R2 of the compounds of formula I listed above also form a novel aspect of the present invention.
The pharmaceutically active compounds of formula (I), the corresponding N-oxides of the group R2 and pharmaceutically acceptable salts thereof of this invention can be prepared by methods known to one skilled in the art.
Typically, compounds of formula (I), can be prepared by coupling of the amino fragment of formula (II)

Scheme-!
General method for synthesis of compounds of formula (I)

In a typical experiment, the amine compound of formula (II), wherein the groups A, B, and R2 have the same meanings as defined hereinbefore is dissolved in a 1:1 mixture of tertahydrofuran and water or a 1:1 mixture of methylene chloride and water. To the solution is added the carboxylic acid compound of formula (III), followed by addition of 1-hydroxybenztriazole (HOBt). The resulting mixture is cooled to a temperature of 0-5° C to which l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.1 Eq.) is added and gradually allowed to warm to room temperature and agitated at this temperature for 24 hours. At the end of
17

In a typical method, morpholine, thiomorpholine, piperidine, 4-benzyl piperazine, pyrrolidine, 1,2,4-triazine, 12,3-benzotriazine, benzyl amine, a heterocycloalkyl or a heteroaryl moiety etc., each one of which corresponds to the group R2 defined hereinbefore is reacted with 3,4-difluoro nitrobenzene in the presence of a base and a solvent to give the corresponding derivative in which the fluorine atom at 4-position is substituted by the group R2. The nitro group in the compound thus obtained is reduced to amino group, which is thereafter protected by a suitable protective group. Reaction of the N-protected compound thus obtained with (R)-glycidyl butyrate in the presence of a strong base like n-butyl lithium leads to formation of the 5-hydroxymethyl oxazolidinone ring. The hydroxy group in the compound thus obtained is converted to sulfonyl derivative, for e.g. a methanesulfonyloxy (mesyl) or a p-toluenesulfonyloxy (tosyl) derivative by reaction with methanesulfonyl chloride or p-toluenesulfonyl chloride respectively. Reaction of the respective mesyl or tosyl derivative with sodium azide gives the corresponding azide, which is converted to the amine compound of formula (II) by standard methods, for e.g. by reaction with a triaryl/trialkyl phosphine, followed by hydrolysis.
The starting carboxylic acid fragments of formula (III), wherein the group Ar has the same meaning as defined hereinearlier are prepared as per the method disclosed in Org. Reactions, 1949, 5, 229-289; Quart. Rev. Chem. Soc, 1954, 8, 355-379; Chem. Rev., 1955, 55, 229-281, and J. Am. Chem. Soc, 1947, 69, 1784-1786. The method is essentially summarized in Scheme-HI.
Scheme-Ill General method for synthesis ofalkane and alkene carboxylic acid s of formula (HI)

In a typical method, the aromatic compound Ar-H, wherein Ar is as defined hereinbefore is reacted with succinic anhydride in the presence of a Lewis acid, such as anhydrous aluminium chloride and in the presence of an anhydrous solvent and the mixture heated to 100° C to give the carboxylic acid derivatives of formula (HI), wherein Q is alkyl of 1-4 carbon atoms.
23

Similarly, compounds of formula (III), wherein Q is an alkene (CH=CH) are prepared by reaction of the aromatic compound Ar-H, wherein Ar is as defined hereinbefore with maleic anhydride under the same conditions mentioned hereinbefore.
Compounds of formula (III), wherein Q is an alkyne (C=C) are prepared by reaction of propiolic acid ester with an aldehyde of formula Ar-CHO in the presence of butyl lithium and in the presence of an aprotic solvent such as THF at -78° C to give the corresponding secondary alcohol, which is oxidized to the keto derivative using manganese dioxide as the oxidizing agent. Saponification gives the carboxylic acid derivative of formula (ID) [ US 4,929,741 (A. Fischili et. al.) ] The synthesis is summarized in Scheme-IV.

against M. tuberculosis including sensitive and resistant strains are summarized in Table-I. The MIC value of a representative preferred Compound No. 30 of formula I against different species of mycobacteria is summarized in Table-II. in vitro Growth Inhibition assay
The ability of the compounds 1-78 of formula (I) of this invention to inhibit the growth of Mycobacterium species was determined by the BACTEC 460 TB system. The reference strain M tuberculosis H37Rv ATCC 27294 was grown in Middlebrook 7H9 broth containing 10% ADC
supplement at 37°C on a rotay shaker at 150 rpm for grown for 7days. The turbidity of the culture was adjusted to 1.0 Mc farland. The BACTEC 7H12B medium vials were seeded with 0.1ml of the 1.0 Mc farland adjusted M. tuberculosis culture. In the control vials 0.1ml of the culture was added after lOOfold dilution of the initial inoculum. Stock solution of lmg/ml of each compound was prepared in DMSO in separate sterile tubes. The compounds were further diluted to concentration of 25 ^g/100 ul, 0.1ml was than added to the 7H12B vial containing mycobacterial culture so that final concentration of the compound 6.25 u.g/ml. The cap in all the vials were cleaned with isopropanyl alcohol and kept in racks. The vials were then incubated at 37°C without shaking. Test vials was read daily on the BACTEC system till the GI of the control vial reached > 30.Once the GI in the control reached 30 AGI (GI = GI (n> - GI („.i) ) was determined for all test and control vials. If AGI of test vial is less than that of the control vial the culture was sensitive to the test compound. in vitro Agar Dilution assay
MIC of compound of formula (I) of this invention against strains of Mycobacterium were determined by a reference agar dilution method as per the NCCLS- M24-T2. recommendations. The compounds were dissolved in DMSO and diluted twofold to obtain ten serial dilutions of each compound. Appropriate volume of compounds were incorporated into duplicate plates of Middlebrook7H10 agar medium supplemented with 10% Middlebrook supplement oleic acid-albumin-dextrose (OADC) enrichment at concentration of 0.03u,g/ml to 16|j,g/ml. Test organisms (mycobacterium strains) were grown in Middle brook 7H9 broth containing 0.05% Tween-80 and 10% ADC supplement. After 7 days of incubation at 37°C the broths were adjusted to the turbidity of 1.0 McFarland standard; the organism were further diluted 10 fold in sterile water containing 0.10% Tween-80. The resulting mycobacterial suspensions were spotted (3-5jxl/spot) onto drug supplemented 7H10 media plates. The plates were sealed and incubated at 37°Cfor 3-4 weeks in upright position. The MIC was recorded as the lowest dilution of the drug that completely inhibited the growth of test organisms. Test isolates included 10 clinical isolates that were generally susceptible to common tubercular agents and 10 strains that were resistant to one or more standard anti tubercular drugs. Appropriate reference strains and control drug was included in each batch of test.
42

in vivo studies:
The efficacy of the compound of formula (I) of this invention was also evaluated in murine model of pulmonary tuberculosis. Mycobacterium tuberculosis cultures grown in Middle brook 7H9 broth containing 0.05% Tween-80 and 10% ADC supplement at 37°C for 7 days on a rotary shaker. For, animal inoculation liquid cultures were declumped by brief sonication and were diluted appropriately in 7H9 broth to obtain a concentration of lxl07CFU's/ 0.2ml. Four-week-old male outbred Swiss albino mice housed in a pathogen free, biosafety level 3 environment within micro isolator cages were used throughout the study. Infections were produced by intravenous inoculation into caudal tail vein of 0.2ml of declumped M. tuberculosis suspension. Following infection, mice were randomly distributed in different groups of six each.
Treatment for initial study was started one day after infection. For, treatment Compound No. 30 of formula I was dissolved in 10% PEG. Isoniazid was dissolved in sterile water. The drugs were prepared each morning prior to administration. Therapy was given 5 days per week for four weeks. All the agents were administered by gavage and were dosed at 50,25,12.5mg / kg of body weight. Control group of infected but untreated mice were killed at the initiation of therapy (early control) or at the end of the treatment period (late control). Mice were sacrificed by cervical dislocation 3-5 days after the administration of the last dose of drug. The spleens and right lung were removed aseptically and homogenized in tissue homogeniser. At least 4 serial tenfold dilution of the homogenate was plated onto selective Middlebrook 7H11 agar plates in duplicate. The colony counts were recorded after incubation at 37°C for 4 weeks. The viable cell counts were converted to Logio values. A compound showing 2 Log reduction in viable counts compared to the controls was considered significant.
The in vivo data for a representative compound of formula (I) is given in Table-II.
Acute toxicity of Compound No. 30 of Chart-I was estimated in mice and the LDo was found to be >1000 mg/kg P. O.
43

Lung Spleen Lung Spleen
1 Compound 30 of Chart-I
50mg/kg 25mg/kg 12.5mg/kg 2.12 2.21 4.34 2.09 2.13 4.30 2.40 2.30 0.20 2.53 2.49 0.26
2 Isoniazid
50mg/kg 25mg/kg 12.5mg/kg 2.03 2.11 2.95 1.92 2.11 2.94 2.49 2.41 1.57 2.70 2.51 1.68
3 Infected early control 4.52 4.62
4 Infected late control 6.57 6.37
a- inoculation of logio:- 7.00 Mycobacteria.
b- mice were dosed 5 day/week for 4 weeks. From day 1 -28.
c- difference in mean logio number CFU from that of early controls.
The compound of formula I of this invention may be administrated to a subject such as a human being or an animal in need of such an administration through any route appropriate to the condition to be treatede. Suitable routes of administration include oral, rectal, nasal, topical (both buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intradermal, intrathecal and epidural).
Pharmaceutical compositions of compound of formula I can be prepared in adjunction with inert pharmaceutically acceptable carriers, which can either be solid or liquid.
Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories and ointments. The solid carriers can be one or more substances which may act also as diluents, flavouring agents, solubilisers, lubricants, suspending agents, binders or tablet disintegrating agents. It can also be finely divided solid which is in admixture with finely divided active compound. Suitable solid carriers are lactose, pectin, dicalcium phosphate, microcrystalline cellulose, sucrose, kaolin, dextrin, gelatin, starch, tragacanth, low melting wax, coca butter and the like.
Liquid preparations include solutions, suspensions and emulsions, e.g. solutions of compound of formula I in water or water-propylene glycol mixture for parenteral injection. Liquid preparations can also be formulated along with non-ionic surfactants and edible oils such as corn, peanut and sesame oils. Aqueous solutions for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours stabilizing and thickening
46

agents, as required. Aqueous suspension for oral use can be made by dispersing the finely divided active component in water with a viscous material, e.g. natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose and othe known suspending agents. The adjuvants may also include preserving agents and anti-oxidants.
Compositions for topical application may take the form of liquids or gels, containing a therapeutically effective concentration of compound of formula I admixed with a dermatologically acceptable carrier.
The pharmaceutical preparations may be in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage can be in the form of tablets, capsules, powdersin vials or ampoules, ointments, gels, creams or any other form. The quantity or concentration of the active compound in such unit dose preparations may be varied or adjusted according to the particular application and potency of the active ingredient.
47

A compound of formula (I) and its pharmaceutical^ acceptable salts

wherein,
A is either hydrogen or fluorine,
B is either hydrogen or fluorine,
A and B together is hydrogen and fluorine,
Ri is a group of formula,

wherein,
Q is either an alkyl group of two carbon atoms, an alkene group of two carbon atoms or
an alkyne group of two carbon atoms
Y is oxygen, sulfur or an amino function of formula NR3
wherein,
R3 is an alkyl group of 1-4 carbon atoms, both saturated and unsaturated, which can be
straight or branched; cycloalkyl of 3-7 carbon atoms; CHO, -COOH, -COOR,; COCR,;
CN; aryl or heteroaryl
wherein,
Rt is an alkyl group of 1-4 carbon atoms, an alkene of 3-6 carbon atoms, an alkyne of
3-6 carbon atoms.
Ar is a substituted phenyl ring or a substituted pyridine ring of formula

—O-R3
or Ar is a five membered ring of formula
48

or Ar is a fused bicyclic phenyl or pyridine ring of formula

wherein,
M is either CH or N
Z is CH, NH, O, or S,
X is a group selected from OR,, NR4R5, N02, SR,, SOOR,, SOONR4R5, F, CI, Br or I,
wherein R4 is as defined hereinbefore, and
and R3 is as defined hereinbefore
R5 is hydrogen or R4
R2 is selected from the groups shown below, and the corresponding N-oxides thereof.

A compound according to Claim 1 wherein in said compound of formula I Aryl is phenyl substituted with (0) or (1) of F, CI, "OCH3, "OH, "NH2, CrC4 alkyl, 0-C(0)-OCH3," N02or"CN.
49

FIELD OF THE INVENTION
The present invention relates to novel compounds belonging to the class of oxazolidinones useful in the treatment of acid fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp. The present invention further relates to methods for preparation of the novel compounds and to pharmaceutical compositions containing the novel compounds useful in the treatment of tuberculosis. BACKGROUND OF THE INVENTION
Tuberculosis (TB), an infectious disease caused by the bacterium Mycobacterium tuberculosis is transmitted mainly through air, affecting most often the lungs. When persons with pulmonary TB cough they produce tiny droplet nuclei containing M. tuberculosis, which remain suspended in air for a prolonged period of time. A person who breathes the air containing the aforesaid droplet nuclei containing M. tuberculosis can become infected with TB.
TB, one of the three major infectious diseases in the priority list of the World Health Organization's (WHO) agenda kills about two million people around the world every year. About six million new cases are reported every year and nearly 20% of adult deaths and 6% of infant deaths are attributable to the disease (C. Dye et. al., J. Am. Med. Ass., 1999, 282, 677-686). About a billion people are expected to be affected by TB by the year 2020, with 35 million likely to succumb to the disease (WHO Fact Sheet No. 104, Global Alliance for TB Drug Development- Executive Summary of the Scientific Blueprint for TB Development : http://www.who.int/inf-fs/en/factl04.html).
With the emergence of the AIDS epidemic and the increase in cases of HIV coupled with TB as well as the continued resistance of M. tuberculosis to isoniazid and rifampicin, the two most powerful anti-tubercular drugs available today there is an urgent need for new anti-tubercular drugs to combat the killer disease (S. H. E. Kaufmann et. al., Trends Microbiol., 1993, 1,2-5 ; B. R. Bloom et. al., N. Engl. J. Med., 1998, 338, 677-678).
Although, many new compounds are becoming available for fighting a number of infectious diseases, the number of such compounds having antimycobacterial activity are few. This could partly be due to the complexity of research involved and partly due to business considerations (B. N. Roy et. al., J. Ind. Chem. Soc, April 2002, 79, 320-335 and references cited therein).
However, renewed thrust in research in the last decade has resulted in development of new antimycobacterial compounds,
a) differing widely in structures,
b) having different mode/mechanism of action,
c) possessing favourable pharmacokinetic properties,
d) which are safe and have low incidence of side-effects, and
e) which provide a cost-effective dosage regimen.
2

Among the aforesaid new compounds, the oxazolidinones first developed during the mid-1980s (W. A. Gregory et. al., J. Med. Chem., 1989, 32,1673-1681 and 1990,33,2569-2578 ; C-H Park et. al., J. Med. Chem., 1992, 35, 1156-1165) are a unique class in themselves. The in vivo results for some of the oxazolidinones show that they are active against various Gram-positive bacteria such as staphylococci, pneumococci and enterococci, including resistant strains such as methicillin-resistant Staphylococcus aureus [MRSA], methicillin-resistant Streptococcus epidermidis [MRSE], penicillin-resistant Streptococcus pneumoniae [PRSP], vancomycin-resistant enterococci [VRE], etc. (B. Riedl et. al., Exp. Opin. Ther. Patents., Ashley Publications Ltd., 1999,9 (5), 625-633 and the references contained therein).
The oxazolidinones inhibit bacterial protein synthesis at a very early step in the initiation of complex formation involved in the process of translating mRNA into protein. The oxazolidinones, in general, are not cross-resistant with any known antibiotic because of this unique mechanism (D. C. Eustice et. al., Antimicrob. Agents Chemother., 1988, 32, 1218 and Biochem. Biophys. Res. Commun., 1988,150. 965).
A feature of the oxazolidinone molecule is that only those compounds, which are enantiomers with a (5S)-acetamidomethyl configuration in the left side of the molecule are known to exhibit antibacterial activity (W. A. Gregory et. al., J. Med. Chem., 1989, 32, 1673-1681). Another feature is that most of such antibacterial compounds invariably carry a (substituted) phenyl ring attached to the nitrogen atom of the oxazolidinone ring in the right side of the molecule (B. Riedl et. al., Exp. Opin. Ther. Patents., Ashley Publications Ltd., 1999, 9 (5), 625-633 and the references contained therein).
The most promising compound among the N-phenyl oxazolidinones, which has been approved for human use is (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidin-yl]methyl]-acetamide), commonly known as linezolid (M. Barbachyn et. al., WO 995/07271). Linezolid possesses good in vitro and in vivo potency against most of the Gram-positive bacteria, including resistant strains {Drugs of the Future, 1996,21.(11), 1116-1123).
The left hand side i. e. position 5- and the right hand side i. e. position 3- respectively of
the oxazolidinone ring nucleus allows for many variations and has resulted in the discovery of a
large number of compounds having antimicrobial and antibacterial properties. Such
representative compounds, albeit not meant to be limiting are disclosed in the following prior art
references. These are:
i) US 4,942,183 (Gregory et. al.) and US 4,948,801 (Carlson et. al.) collectively disclose
certain 3-substituted phenyl- 5-aminomethyl oxazolidinones, possessing useful
antibacterial activity, ii) US 5,529,998 (Habich et. al.) discloses certain 3-benzoxazoyl- and benzothiazolyl-5-
acetyl amino methyl oxazolidinones, useful as antibacterial medicaments.
3

iii) US 5,565,571, US 5,654,428, US 5,756,732, US 5,801,246 and US 5,929,248 (Barbachyn et. al.) collectively disclose several substituted aryl and heteroaryl phenyloxazolidinones carrying an acetyl aminomethyl function at the 5-position, specifically oxazolidinones having an aryl or heteroaryl group at the para position of the 3-phenyl ring and additional substituents at the meta positions of the 3-phenyl ring, which are useful as antibacterials.
iv) US 5,652,238 (Brickner et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a hydroxyl acetyl piperazine moiety, active against various Gram-positive bacteria such as staphylococci, pneumococci and enterococci, as well as anerobic organisms such as bacteroides and Clostridia species as well as acid-fast organisms such as Mycobacterium tuberculosis.
v) US 5,684,023 (Riedl et. al.) discloses certain 3- benzofuranyl- and benzothienyl oxazolidinones, carrying an azido, hydroxy or acetyl aminomethyl group at the 5-position, useful as antibacterial medicaments.
vi) US 5,688,792 (Barbachyn et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a (substituted)-morpholine. Such compounds are useful for treatment of microbial infections caused by staphylococci, streptococci, enterococci, Bacteroides spp., Clostridia spp., Mycobacterium tuberculosis, Mycobacterium avium or Mycobacterium spp.
vii) US 5,719,154 (Tucker et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, the said substitution being a pyrimidinyl or pyradazinyl group. Such compounds are useful as antimicrobial agents.
viii) US 5,736,545 (Gadwood et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, the substitution being a five membered heterocycle ring, in particular an azolyl ring. Such compounds are useful in the treatment of microbial infections.
ix) US 5,792,765 (Riedl. et. al.) discloses certain substituted 5-acetyl aminomethyl-3-substituted phenyloxazolidinones, the substitution being a heterocyclic moiety, useful as antibacterial medicaments.
x) US 5,861,413 (Habich et. al.) discloses certain 2-oxo and 2-thio-l,2-dihydroxyqoinolinyl-1-oxazolidinones, useful as antibacterial medicaments.
xi) US 5,880,118 (Barbachyn et. al.) discloses certain substituted 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a
4

substituted thiomorholine moiety i. e. oxazine and thiazine derivatives, useful for treatment of microbial infections caused by staphylococci, streptococci, enterococci, Bacteroides spp., Clostridia spp., Mycobacterium tuberculosis, Mycobacterium avium or Mycobacterium spp.
xii) US 5,910,504 and US 6,124,334 (Hutchinson et. al.) collectively disclose certain substituted 5-acetyl aminomethyl-3- phenyloxazolidinones substituted at the para position of the 3-phenyl ring with a heteroaromatic moiety, which is five membered having one to four nitrogen atoms or alternatively, a benzoannulated five-membered heteroaromatic ring having one to four nitrogen atoms, useful as antibacterials.
xiii) US 6,069,160 (Stolle et. al.) discloses certain substituted 5-acetyl aminomethyl-3-benzocyclopentaneoxazolidinones, containing an heteroatom, useful as antibacterial medicaments.
xiv) US 6,227,868 Bl and US 6,410,728 (Sciotti et. al.) collectively disclose certain 5-acetyl aminomethyl-3-phenyloxazolidinones carrying an acetylenic moiety on the 3-phenyl ring, useful for treating bacterial infections, psoriasis, arthritis and toxicity due to chemotherapy.
xv) WO 93/23384 (Hutchinson et. al.) discloses certain substituted 5-acetyl aminomethyl-3 -phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, useful for treatment of microbial infections caused by staphylococci, streptococci, as well as anaerobic organisms such as bacteroides and Clostridia species and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium.
xvi) WO 97/10223 (Gadwood et. al.) discloses certain substituted 5-acetyl aminomethyl-3-aminoaryl oxazolidinone N-oxide compounds, which are exceedingly water soluble and useful in preparation of pharmaceutical compositions for combating a number of human and veterinary pathogens, staphylococci, streptococci, as well as anaerobic organisms such as bacteroides and Clostridia species and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium, Mycobacterium spp. and Mycoplasma spp.
xvii) WO 98/01446 and WO 98/01447 (Betts et. al.) collectively disclose certain substituted 5-acetyl aminomethyl3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, the substitution being a six-membered heteroaryl ring containing two or three ring nitrogen atoms as the only ring heteroatoms, useful as antibacterial agents.
xviii) WO 99/02525 (Thomasco et. al.) discloses certain substituted 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted by a thiadiazolyl or oxadiazolyl moiety, useful as
5

antimicrobial agents, effective against a number of human and veterinary pathogens, including Gram-positive and Gram-negative aerobic bacteria.
xix) WO 99/37630 (Gordeev et. al.) discloses oxazolidinone combinatorial libraries, compositionscontaining the same and methods of preparation thereof involving solid phase synthesis, which provides the said compounds for high-throughput screening.
xx) W099/37641 (Bartel. et. al.) discloses certain substituted 5-acetyl aminomethyl-3-bicyclene-substituted oxazolidinones, useful as antibacterial medicaments.
xxi) WO 01/09107 (Gordeev et. al.) discloses certain 3-heteroaryl-5-acetyl aminomethyl oxazolidinones, substituted by a thioacyl, aminocarbonyl, alkoxycarbonyl, aminothiocarbonyl, alkoxythiocarbonyl and alkylthiocarbonyl group, useful in treating or preventing an infectious disorder in humans or animals.
xxii) WO 01/42242 (Paget et. al.) discloses certain substituted 5-acetyl aminomethyl 3-substituted phenyloxazolidinones, the substitution being a bicyclic heterocyclic system, useful as antibacterial agents.
xxiii) WO 02/06278 (Mehta et. al) discloses certain substituted 3-phenyl oxazolidinones and to process for synthesis of the same, the said compounds useful as antibacterial agents, effective against a large number of human and veterinary pathogens, including Gram-positive bacteria and acid fast organisms such as Mycobacterium tuberculosis.
xxiv) WO 02/20515 (Madar et. al.) discloses heterocyclic phenyloxazolidinones, useful for treating bacterial infections. However, only a few of the disclosures described hereinbefore provide compounds that
can be used as antimycobacterials, while most of the others are silent about the antimycobacterial
activity of the disclosed compounds.
A need, therefore, exists for new compounds possessing potent antimycobacterial
properties for treatment of TB, which as mentioned hereinearlier is assuming alarming
proportions.
OBJECTS OF THE INVENTION
It is thus the basic object of the present invention to synthesize, identify and provide new
compounds belonging to the class of oxazolidinones, possessing potent antimycobacterial
properties especially for treatment of acid fast organisms such as Mycobacterium tuberculosis,
Mycobacterium avium-intracellular complex, M. fortuitum and M. kansai.
Another object is directed to providing antimycobacterial pharmaceutical composition
effective in inhibiting/treating the generation of mycobacterial conditions/cells including
Mycotacterium tuberculosis, drug resistant Mycobacterium tuberculosis, Mycobacterium avium-intracellular complex, M fortuitum and Mkansai.
6

Yet another object is directed to providing a method of treating/inhibiting mycobacterial cells/conditions involving the administrations of effective amount of the novel antimycobacterial compound and/or its salts /composition of the invention. SUMMARY OF THE INVENTION
Thus according to the basic aspect of the present invention there is provided compound of formula (I) and its pharmaceutically acceptable salts thereof

R is an alkane of 1-4 carbon atoms, an alkene of 3-6 carbon atoms, an alkyne of 3-6 carbon
atoms, and
Ar is an aromatic carbocycle represented by

7

wherein,
X is OR4, NR4R5, N02, SR4, SOOR4, SOONR4R5, Br, CI, F, or I,
M is-CHorN,and
Zis-CH,-NH,OorS
and wherein,
R3 and R4 are as described hereinbefore, and
R5 is H, or same as R4, and
R.2 is selected from the groups shown below, and the corressponding N-oxides thereof

Heteroaryl or Heterocycloalkyl wherein K is O, S, SO, S02, or CH2
According to another aspect of the invention there is provided a pharmaceutical
composition comprising:
i) atleast one of an antimycobacterially effective amounts of compound of formula I and
pharmaceutically acceptable salts there of; and ii) a pharmaceutically acceptable carrier.
According to yet another aspect of the present invention there is provided a method of inhibiting growth of mycobacterial cells such as Mycobacterium tuberculosis, drug resistant Mycobacterium tuberculosis, Mycobacterium avium-intracellular complex, M. fortuitum and M.kansai.,comprising administering an antimycobacterially effective amount of the compound of formula I and/or pharmaceutically acceptable salts thereof.
8

According to yet another aspect of the present invention there is provided a method of treating mycobacterial conditions such as Mycobacterium tuberculosis, drug resistant Mycobacterium tuberculosis, Mycobacterium avium-intracellular complex, M. fortuitum and M kansai, comprising administering an antimycobacterially effective amount of the compound of formula I and/or pharmaceutically acceptable salts thereof.
According to another aspect, there is provided a process for the manufacture of the compound of formula I or its pharmaceutically acceptable salts comprising : coupling the amino fragments of compound of formula II with the carboxylic acid fragment of formula III.
The above disclosed compound of formula I its pharmaceutically acceptable salts thereof are found to have antimycobacterial properties and the same in admixture with pharmaceutically active additives, an be administrated orally or paranterally for treatement of mycobacterial conditions especially TB. DETAILED DESCRIPTION OF THE INVENTION
In the pharmaceutically active compound of formula (I) of this invention,

the definition of the symbols and groups A, B, Rt and R2 are as follows :
A is either hydrogen or fluorine,
B is either hydrogen or fluorine,
A and B together is hydrogen and fluorine,
When A is hydrogen, B is fluorine and vice-versa.
R1 represents a group of formula,

Q is either an alkyl group of two carbon atoms (CH2-CH2), an alkene group of two to carbon atoms (CH=CH), or an alkyne group of two carbon atoms (C=C)
9

Y can either be oxygen, sulfur or an amino function of formula NR3, wherein
R3 is an alkyl group of 1-4 carbon atoms, both saturated and unsaturated, which can be straight or
branched. Suitable alkyl groups are methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl, tert-
butyl, ethylene, propylene, 1, butene, both the geometric isomers of 2-butene i. e.(cis)-2-butene
and (trans)-2-butene, and iso-butylene. or
R3 is a cycloalkyl group of 3-7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl, or
R3 is a carboxylic acid group (-COOH) or a carboxylic acid ester of formula-COOR4, wherein
R4 is H, an alkyl group of 1-4 carbon atoms, an alkene of 3-6 carbon atoms, an alkyne of 3-6
carbon atoms.
R3 is further an aldehyde (-CHO), an acetyl group (-COCR4), wherein R4 is as mentioned
hereinbefore or R3 is a nitrile (CN), aryl or heteroaryl, wherein
Aryl is phenyl substituted with (0) or (1) of-F, -CI, -OCH3, -OH, -NH2, -CrC4 alkyl, -O-C(O)-
OCH3,-N02or-CN,and
Heteroaryl
or Ar is a five membered ring of formula
or Ar is a fused bicyclic phenyl or pyridine ring of formula
10
The group Ar is a substituted phenyl ring or a substituted pyridine ring of formula

wherein,
M is either CH or N; Z is -CH, -NH, O or S and R3 is as defined hereinbefore,
X is a group selected from OR4, NR4R5, N02, SR4, SOOR4, SOONR4R5, F, CI, Br or I, wherein
R4 is as defined hereinbefore, and
R5 is hydrogen or R4.
R2 is selected from the groups shown below, and the corresponding N-oxides thereof.

78. (S) - N -[ [ 3 - ( 3 - fluoro - 4 - thiomorpholinylphenyl ) - 2 — oxo - 5 - oxazolidinyl ] methyl ] - 4 - ( 2,4 - dimethyl- 4 ethylphenyl) - 4 - oxobutanamide.
The respective N-oxides of the group R2 of the compounds of formula I listed above also form a novel aspect of the present invention.
The pharmaceutically active compounds of formula (I), the corresponding N-oxides of the group R2 and pharmaceutically acceptable salts thereof of this invention can be prepared by methods known to one skilled in the art.
Typically, compounds of formula (I), can be prepared by coupling of the amino fragment of formula (II)

Scheme-!
General method for synthesis of compounds of formula (I)

In a typical experiment, the amine compound of formula (II), wherein the groups A, B, and R2 have the same meanings as defined hereinbefore is dissolved in a 1:1 mixture of tertahydrofuran and water or a 1:1 mixture of methylene chloride and water. To the solution is added the carboxylic acid compound of formula (III), followed by addition of 1-hydroxybenztriazole (HOBt). The resulting mixture is cooled to a temperature of 0-5° C to which l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.1 Eq.) is added and gradually allowed to warm to room temperature and agitated at this temperature for 24 hours. At the end of
17

In a typical method, morpholine, thiomorpholine, piperidine, 4-benzyl piperazine, pyrrolidine, 1,2,4-triazine, 12,3-benzotriazine, benzyl amine, a heterocycloalkyl or a heteroaryl moiety etc., each one of which corresponds to the group R2 defined hereinbefore is reacted with 3,4-difluoro nitrobenzene in the presence of a base and a solvent to give the corresponding derivative in which the fluorine atom at 4-position is substituted by the group R2. The nitro group in the compound thus obtained is reduced to amino group, which is thereafter protected by a suitable protective group. Reaction of the N-protected compound thus obtained with (R)-glycidyl butyrate in the presence of a strong base like n-butyl lithium leads to formation of the 5-hydroxymethyl oxazolidinone ring. The hydroxy group in the compound thus obtained is converted to sulfonyl derivative, for e.g. a methanesulfonyloxy (mesyl) or a p-toluenesulfonyloxy (tosyl) derivative by reaction with methanesulfonyl chloride or p-toluenesulfonyl chloride respectively. Reaction of the respective mesyl or tosyl derivative with sodium azide gives the corresponding azide, which is converted to the amine compound of formula (II) by standard methods, for e.g. by reaction with a triaryl/trialkyl phosphine, followed by hydrolysis.
The starting carboxylic acid fragments of formula (III), wherein the group Ar has the same meaning as defined hereinearlier are prepared as per the method disclosed in Org. Reactions, 1949, 5, 229-289; Quart. Rev. Chem. Soc, 1954, 8, 355-379; Chem. Rev., 1955, 55, 229-281, and J. Am. Chem. Soc, 1947, 69, 1784-1786. The method is essentially summarized in Scheme-HI.
Scheme-Ill General method for synthesis ofalkane and alkene carboxylic acid s of formula (HI)

In a typical method, the aromatic compound Ar-H, wherein Ar is as defined hereinbefore is reacted with succinic anhydride in the presence of a Lewis acid, such as anhydrous aluminium chloride and in the presence of an anhydrous solvent and the mixture heated to 100° C to give the carboxylic acid derivatives of formula (HI), wherein Q is alkyl of 1-4 carbon atoms.
23

Similarly, compounds of formula (III), wherein Q is an alkene (CH=CH) are prepared by reaction of the aromatic compound Ar-H, wherein Ar is as defined hereinbefore with maleic anhydride under the same conditions mentioned hereinbefore.
Compounds of formula (III), wherein Q is an alkyne (C=C) are prepared by reaction of propiolic acid ester with an aldehyde of formula Ar-CHO in the presence of butyl lithium and in the presence of an aprotic solvent such as THF at -78° C to give the corresponding secondary alcohol, which is oxidized to the keto derivative using manganese dioxide as the oxidizing agent. Saponification gives the carboxylic acid derivative of formula (ID) [ US 4,929,741 (A. Fischili et. al.) ] The synthesis is summarized in Scheme-IV.

against M. tuberculosis including sensitive and resistant strains are summarized in Table-I. The MIC value of a representative preferred Compound No. 30 of formula I against different species of mycobacteria is summarized in Table-II. in vitro Growth Inhibition assay
The ability of the compounds 1-78 of formula (I) of this invention to inhibit the growth of Mycobacterium species was determined by the BACTEC 460 TB system. The reference strain M tuberculosis H37Rv ATCC 27294 was grown in Middlebrook 7H9 broth containing 10% ADC
supplement at 37°C on a rotay shaker at 150 rpm for grown for 7days. The turbidity of the culture was adjusted to 1.0 Mc farland. The BACTEC 7H12B medium vials were seeded with 0.1ml of the 1.0 Mc farland adjusted M. tuberculosis culture. In the control vials 0.1ml of the culture was added after lOOfold dilution of the initial inoculum. Stock solution of lmg/ml of each compound was prepared in DMSO in separate sterile tubes. The compounds were further diluted to concentration of 25 ^g/100 ul, 0.1ml was than added to the 7H12B vial containing mycobacterial culture so that final concentration of the compound 6.25 u.g/ml. The cap in all the vials were cleaned with isopropanyl alcohol and kept in racks. The vials were then incubated at 37°C without shaking. Test vials was read daily on the BACTEC system till the GI of the control vial reached > 30.Once the GI in the control reached 30 AGI (GI = GI (n> - GI („.i) ) was determined for all test and control vials. If AGI of test vial is less than that of the control vial the culture was sensitive to the test compound. in vitro Agar Dilution assay
MIC of compound of formula (I) of this invention against strains of Mycobacterium were determined by a reference agar dilution method as per the NCCLS- M24-T2. recommendations. The compounds were dissolved in DMSO and diluted twofold to obtain ten serial dilutions of each compound. Appropriate volume of compounds were incorporated into duplicate plates of Middlebrook7H10 agar medium supplemented with 10% Middlebrook supplement oleic acid-albumin-dextrose (OADC) enrichment at concentration of 0.03u,g/ml to 16|j,g/ml. Test organisms (mycobacterium strains) were grown in Middle brook 7H9 broth containing 0.05% Tween-80 and 10% ADC supplement. After 7 days of incubation at 37°C the broths were adjusted to the turbidity of 1.0 McFarland standard; the organism were further diluted 10 fold in sterile water containing 0.10% Tween-80. The resulting mycobacterial suspensions were spotted (3-5jxl/spot) onto drug supplemented 7H10 media plates. The plates were sealed and incubated at 37°Cfor 3-4 weeks in upright position. The MIC was recorded as the lowest dilution of the drug that completely inhibited the growth of test organisms. Test isolates included 10 clinical isolates that were generally susceptible to common tubercular agents and 10 strains that were resistant to one or more standard anti tubercular drugs. Appropriate reference strains and control drug was included in each batch of test.
42

in vivo studies:
The efficacy of the compound of formula (I) of this invention was also evaluated in murine model of pulmonary tuberculosis. Mycobacterium tuberculosis cultures grown in Middle brook 7H9 broth containing 0.05% Tween-80 and 10% ADC supplement at 37°C for 7 days on a rotary shaker. For, animal inoculation liquid cultures were declumped by brief sonication and were diluted appropriately in 7H9 broth to obtain a concentration of lxl07CFU's/ 0.2ml. Four-week-old male outbred Swiss albino mice housed in a pathogen free, biosafety level 3 environment within micro isolator cages were used throughout the study. Infections were produced by intravenous inoculation into caudal tail vein of 0.2ml of declumped M. tuberculosis suspension. Following infection, mice were randomly distributed in different groups of six each.
Treatment for initial study was started one day after infection. For, treatment Compound No. 30 of formula I was dissolved in 10% PEG. Isoniazid was dissolved in sterile water. The drugs were prepared each morning prior to administration. Therapy was given 5 days per week for four weeks. All the agents were administered by gavage and were dosed at 50,25,12.5mg / kg of body weight. Control group of infected but untreated mice were killed at the initiation of therapy (early control) or at the end of the treatment period (late control). Mice were sacrificed by cervical dislocation 3-5 days after the administration of the last dose of drug. The spleens and right lung were removed aseptically and homogenized in tissue homogeniser. At least 4 serial tenfold dilution of the homogenate was plated onto selective Middlebrook 7H11 agar plates in duplicate. The colony counts were recorded after incubation at 37°C for 4 weeks. The viable cell counts were converted to Logio values. A compound showing 2 Log reduction in viable counts compared to the controls was considered significant.
The in vivo data for a representative compound of formula (I) is given in Table-II.
Acute toxicity of Compound No. 30 of Chart-I was estimated in mice and the LDo was found to be >1000 mg/kg P. O.
43

Lung Spleen Lung Spleen
1 Compound 30 of Chart-I
50mg/kg 25mg/kg 12.5mg/kg 2.12 2.21 4.34 2.09 2.13 4.30 2.40 2.30 0.20 2.53 2.49 0.26
2 Isoniazid
50mg/kg 25mg/kg 12.5mg/kg 2.03 2.11 2.95 1.92 2.11 2.94 2.49 2.41 1.57 2.70 2.51 1.68
3 Infected early control 4.52 4.62
4 Infected late control 6.57 6.37
a- inoculation of logio:- 7.00 Mycobacteria.
b- mice were dosed 5 day/week for 4 weeks. From day 1 -28.
c- difference in mean logio number CFU from that of early controls.
The compound of formula I of this invention may be administrated to a subject such as a human being or an animal in need of such an administration through any route appropriate to the condition to be treatede. Suitable routes of administration include oral, rectal, nasal, topical (both buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intradermal, intrathecal and epidural).
Pharmaceutical compositions of compound of formula I can be prepared in adjunction with inert pharmaceutically acceptable carriers, which can either be solid or liquid.
Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories and ointments. The solid carriers can be one or more substances which may act also as diluents, flavouring agents, solubilisers, lubricants, suspending agents, binders or tablet disintegrating agents. It can also be finely divided solid which is in admixture with finely divided active compound. Suitable solid carriers are lactose, pectin, dicalcium phosphate, microcrystalline cellulose, sucrose, kaolin, dextrin, gelatin, starch, tragacanth, low melting wax, coca butter and the like.
Liquid preparations include solutions, suspensions and emulsions, e.g. solutions of compound of formula I in water or water-propylene glycol mixture for parenteral injection. Liquid preparations can also be formulated along with non-ionic surfactants and edible oils such as corn, peanut and sesame oils. Aqueous solutions for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours stabilizing and thickening
46

agents, as required. Aqueous suspension for oral use can be made by dispersing the finely divided active component in water with a viscous material, e.g. natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose and othe known suspending agents. The adjuvants may also include preserving agents and anti-oxidants.
Compositions for topical application may take the form of liquids or gels, containing a therapeutically effective concentration of compound of formula I admixed with a dermatologically acceptable carrier.
The pharmaceutical preparations may be in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage can be in the form of tablets, capsules, powdersin vials or ampoules, ointments, gels, creams or any other form. The quantity or concentration of the active compound in such unit dose preparations may be varied or adjusted according to the particular application and potency of the active ingredient.
47

A compound of formula (I) and its pharmaceutical^ acceptable salts

wherein,
A is either hydrogen or fluorine,
B is either hydrogen or fluorine,
A and B together is hydrogen and fluorine,
Ri is a group of formula,

wherein,
Q is either an alkyl group of two carbon atoms, an alkene group of two carbon atoms or
an alkyne group of two carbon atoms
Y is oxygen, sulfur or an amino function of formula NR3
wherein,
R3 is an alkyl group of 1-4 carbon atoms, both saturated and unsaturated, which can be
straight or branched; cycloalkyl of 3-7 carbon atoms; CHO, -COOH, -COOR,; COCR,;
CN; aryl or heteroaryl
wherein,
Rt is an alkyl group of 1-4 carbon atoms, an alkene of 3-6 carbon atoms, an alkyne of
3-6 carbon atoms.
Ar is a substituted phenyl ring or a substituted pyridine ring of formula

—O-R3
or Ar is a five membered ring of formula
48

or Ar is a fused bicyclic phenyl or pyridine ring of formula

wherein,
M is either CH or N
Z is CH, NH, O, or S,
X is a group selected from OR,, NR4R5, N02, SR,, SOOR,, SOONR4R5, F, CI, Br or I,
wherein R4 is as defined hereinbefore, and
and R3 is as defined hereinbefore
R5 is hydrogen or R4
R2 is selected from the groups shown below, and the corresponding N-oxides thereof.

A compound according to Claim 1 wherein in said compound of formula I Aryl is phenyl substituted with (0) or (1) of F, CI, "OCH3, "OH, "NH2, CrC4 alkyl, 0-C(0)-OCH3," N02or"CN.
49

FIELD OF THE INVENTION
The present invention relates to novel compounds belonging to the class of oxazolidinones useful in the treatment of acid fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp. The present invention further relates to methods for preparation of the novel compounds and to pharmaceutical compositions containing the novel compounds useful in the treatment of tuberculosis. BACKGROUND OF THE INVENTION
Tuberculosis (TB), an infectious disease caused by the bacterium Mycobacterium tuberculosis is transmitted mainly through air, affecting most often the lungs. When persons with pulmonary TB cough they produce tiny droplet nuclei containing M. tuberculosis, which remain suspended in air for a prolonged period of time. A person who breathes the air containing the aforesaid droplet nuclei containing M. tuberculosis can become infected with TB.
TB, one of the three major infectious diseases in the priority list of the World Health Organization's (WHO) agenda kills about two million people around the world every year. About six million new cases are reported every year and nearly 20% of adult deaths and 6% of infant deaths are attributable to the disease (C. Dye et. al., J. Am. Med. Ass., 1999, 282, 677-686). About a billion people are expected to be affected by TB by the year 2020, with 35 million likely to succumb to the disease (WHO Fact Sheet No. 104, Global Alliance for TB Drug Development- Executive Summary of the Scientific Blueprint for TB Development : http://www.who.int/inf-fs/en/factl04.html).
With the emergence of the AIDS epidemic and the increase in cases of HIV coupled with TB as well as the continued resistance of M. tuberculosis to isoniazid and rifampicin, the two most powerful anti-tubercular drugs available today there is an urgent need for new anti-tubercular drugs to combat the killer disease (S. H. E. Kaufmann et. al., Trends Microbiol., 1993, 1,2-5 ; B. R. Bloom et. al., N. Engl. J. Med., 1998, 338, 677-678).
Although, many new compounds are becoming available for fighting a number of infectious diseases, the number of such compounds having antimycobacterial activity are few. This could partly be due to the complexity of research involved and partly due to business considerations (B. N. Roy et. al., J. Ind. Chem. Soc, April 2002, 79, 320-335 and references cited therein).
However, renewed thrust in research in the last decade has resulted in development of new antimycobacterial compounds,
a) differing widely in structures,
b) having different mode/mechanism of action,
c) possessing favourable pharmacokinetic properties,
d) which are safe and have low incidence of side-effects, and
e) which provide a cost-effective dosage regimen.
2

Among the aforesaid new compounds, the oxazolidinones first developed during the mid-1980s (W. A. Gregory et. al., J. Med. Chem., 1989, 32,1673-1681 and 1990,33,2569-2578 ; C-H Park et. al., J. Med. Chem., 1992, 35, 1156-1165) are a unique class in themselves. The in vivo results for some of the oxazolidinones show that they are active against various Gram-positive bacteria such as staphylococci, pneumococci and enterococci, including resistant strains such as methicillin-resistant Staphylococcus aureus [MRSA], methicillin-resistant Streptococcus epidermidis [MRSE], penicillin-resistant Streptococcus pneumoniae [PRSP], vancomycin-resistant enterococci [VRE], etc. (B. Riedl et. al., Exp. Opin. Ther. Patents., Ashley Publications Ltd., 1999,9 (5), 625-633 and the references contained therein).
The oxazolidinones inhibit bacterial protein synthesis at a very early step in the initiation of complex formation involved in the process of translating mRNA into protein. The oxazolidinones, in general, are not cross-resistant with any known antibiotic because of this unique mechanism (D. C. Eustice et. al., Antimicrob. Agents Chemother., 1988, 32, 1218 and Biochem. Biophys. Res. Commun., 1988,150. 965).
A feature of the oxazolidinone molecule is that only those compounds, which are enantiomers with a (5S)-acetamidomethyl configuration in the left side of the molecule are known to exhibit antibacterial activity (W. A. Gregory et. al., J. Med. Chem., 1989, 32, 1673-1681). Another feature is that most of such antibacterial compounds invariably carry a (substituted) phenyl ring attached to the nitrogen atom of the oxazolidinone ring in the right side of the molecule (B. Riedl et. al., Exp. Opin. Ther. Patents., Ashley Publications Ltd., 1999, 9 (5), 625-633 and the references contained therein).
The most promising compound among the N-phenyl oxazolidinones, which has been approved for human use is (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidin-yl]methyl]-acetamide), commonly known as linezolid (M. Barbachyn et. al., WO 995/07271). Linezolid possesses good in vitro and in vivo potency against most of the Gram-positive bacteria, including resistant strains {Drugs of the Future, 1996,21.(11), 1116-1123).
The left hand side i. e. position 5- and the right hand side i. e. position 3- respectively of
the oxazolidinone ring nucleus allows for many variations and has resulted in the discovery of a
large number of compounds having antimicrobial and antibacterial properties. Such
representative compounds, albeit not meant to be limiting are disclosed in the following prior art
references. These are:
i) US 4,942,183 (Gregory et. al.) and US 4,948,801 (Carlson et. al.) collectively disclose
certain 3-substituted phenyl- 5-aminomethyl oxazolidinones, possessing useful
antibacterial activity, ii) US 5,529,998 (Habich et. al.) discloses certain 3-benzoxazoyl- and benzothiazolyl-5-
acetyl amino methyl oxazolidinones, useful as antibacterial medicaments.
3

iii) US 5,565,571, US 5,654,428, US 5,756,732, US 5,801,246 and US 5,929,248 (Barbachyn et. al.) collectively disclose several substituted aryl and heteroaryl phenyloxazolidinones carrying an acetyl aminomethyl function at the 5-position, specifically oxazolidinones having an aryl or heteroaryl group at the para position of the 3-phenyl ring and additional substituents at the meta positions of the 3-phenyl ring, which are useful as antibacterials.
iv) US 5,652,238 (Brickner et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a hydroxyl acetyl piperazine moiety, active against various Gram-positive bacteria such as staphylococci, pneumococci and enterococci, as well as anerobic organisms such as bacteroides and Clostridia species as well as acid-fast organisms such as Mycobacterium tuberculosis.
v) US 5,684,023 (Riedl et. al.) discloses certain 3- benzofuranyl- and benzothienyl oxazolidinones, carrying an azido, hydroxy or acetyl aminomethyl group at the 5-position, useful as antibacterial medicaments.
vi) US 5,688,792 (Barbachyn et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a (substituted)-morpholine. Such compounds are useful for treatment of microbial infections caused by staphylococci, streptococci, enterococci, Bacteroides spp., Clostridia spp., Mycobacterium tuberculosis, Mycobacterium avium or Mycobacterium spp.
vii) US 5,719,154 (Tucker et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, the said substitution being a pyrimidinyl or pyradazinyl group. Such compounds are useful as antimicrobial agents.
viii) US 5,736,545 (Gadwood et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, the substitution being a five membered heterocycle ring, in particular an azolyl ring. Such compounds are useful in the treatment of microbial infections.
ix) US 5,792,765 (Riedl. et. al.) discloses certain substituted 5-acetyl aminomethyl-3-substituted phenyloxazolidinones, the substitution being a heterocyclic moiety, useful as antibacterial medicaments.
x) US 5,861,413 (Habich et. al.) discloses certain 2-oxo and 2-thio-l,2-dihydroxyqoinolinyl-1-oxazolidinones, useful as antibacterial medicaments.
xi) US 5,880,118 (Barbachyn et. al.) discloses certain substituted 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a
4

substituted thiomorholine moiety i. e. oxazine and thiazine derivatives, useful for treatment of microbial infections caused by staphylococci, streptococci, enterococci, Bacteroides spp., Clostridia spp., Mycobacterium tuberculosis, Mycobacterium avium or Mycobacterium spp.
xii) US 5,910,504 and US 6,124,334 (Hutchinson et. al.) collectively disclose certain substituted 5-acetyl aminomethyl-3- phenyloxazolidinones substituted at the para position of the 3-phenyl ring with a heteroaromatic moiety, which is five membered having one to four nitrogen atoms or alternatively, a benzoannulated five-membered heteroaromatic ring having one to four nitrogen atoms, useful as antibacterials.
xiii) US 6,069,160 (Stolle et. al.) discloses certain substituted 5-acetyl aminomethyl-3-benzocyclopentaneoxazolidinones, containing an heteroatom, useful as antibacterial medicaments.
xiv) US 6,227,868 Bl and US 6,410,728 (Sciotti et. al.) collectively disclose certain 5-acetyl aminomethyl-3-phenyloxazolidinones carrying an acetylenic moiety on the 3-phenyl ring, useful for treating bacterial infections, psoriasis, arthritis and toxicity due to chemotherapy.
xv) WO 93/23384 (Hutchinson et. al.) discloses certain substituted 5-acetyl aminomethyl-3 -phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, useful for treatment of microbial infections caused by staphylococci, streptococci, as well as anaerobic organisms such as bacteroides and Clostridia species and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium.
xvi) WO 97/10223 (Gadwood et. al.) discloses certain substituted 5-acetyl aminomethyl-3-aminoaryl oxazolidinone N-oxide compounds, which are exceedingly water soluble and useful in preparation of pharmaceutical compositions for combating a number of human and veterinary pathogens, staphylococci, streptococci, as well as anaerobic organisms such as bacteroides and Clostridia species and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium, Mycobacterium spp. and Mycoplasma spp.
xvii) WO 98/01446 and WO 98/01447 (Betts et. al.) collectively disclose certain substituted 5-acetyl aminomethyl3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, the substitution being a six-membered heteroaryl ring containing two or three ring nitrogen atoms as the only ring heteroatoms, useful as antibacterial agents.
xviii) WO 99/02525 (Thomasco et. al.) discloses certain substituted 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted by a thiadiazolyl or oxadiazolyl moiety, useful as
5

antimicrobial agents, effective against a number of human and veterinary pathogens, including Gram-positive and Gram-negative aerobic bacteria.
xix) WO 99/37630 (Gordeev et. al.) discloses oxazolidinone combinatorial libraries, compositionscontaining the same and methods of preparation thereof involving solid phase synthesis, which provides the said compounds for high-throughput screening.
xx) W099/37641 (Bartel. et. al.) discloses certain substituted 5-acetyl aminomethyl-3-bicyclene-substituted oxazolidinones, useful as antibacterial medicaments.
xxi) WO 01/09107 (Gordeev et. al.) discloses certain 3-heteroaryl-5-acetyl aminomethyl oxazolidinones, substituted by a thioacyl, aminocarbonyl, alkoxycarbonyl, aminothiocarbonyl, alkoxythiocarbonyl and alkylthiocarbonyl group, useful in treating or preventing an infectious disorder in humans or animals.
xxii) WO 01/42242 (Paget et. al.) discloses certain substituted 5-acetyl aminomethyl 3-substituted phenyloxazolidinones, the substitution being a bicyclic heterocyclic system, useful as antibacterial agents.
xxiii) WO 02/06278 (Mehta et. al) discloses certain substituted 3-phenyl oxazolidinones and to process for synthesis of the same, the said compounds useful as antibacterial agents, effective against a large number of human and veterinary pathogens, including Gram-positive bacteria and acid fast organisms such as Mycobacterium tuberculosis.
xxiv) WO 02/20515 (Madar et. al.) discloses heterocyclic phenyloxazolidinones, useful for treating bacterial infections. However, only a few of the disclosures described hereinbefore provide compounds that
can be used as antimycobacterials, while most of the others are silent about the antimycobacterial
activity of the disclosed compounds.
A need, therefore, exists for new compounds possessing potent antimycobacterial
properties for treatment of TB, which as mentioned hereinearlier is assuming alarming
proportions.
OBJECTS OF THE INVENTION
It is thus the basic object of the present invention to synthesize, identify and provide new
compounds belonging to the class of oxazolidinones, possessing potent antimycobacterial
properties especially for treatment of acid fast organisms such as Mycobacterium tuberculosis,
Mycobacterium avium-intracellular complex, M. fortuitum and M. kansai.
Another object is directed to providing antimycobacterial pharmaceutical composition
effective in inhibiting/treating the generation of mycobacterial conditions/cells including
Mycotacterium tuberculosis, drug resistant Mycobacterium tuberculosis, Mycobacterium avium-intracellular complex, M fortuitum and Mkansai.
6

Yet another object is directed to providing a method of treating/inhibiting mycobacterial cells/conditions involving the administrations of effective amount of the novel antimycobacterial compound and/or its salts /composition of the invention. SUMMARY OF THE INVENTION
Thus according to the basic aspect of the present invention there is provided compound of formula (I) and its pharmaceutically acceptable salts thereof

R is an alkane of 1-4 carbon atoms, an alkene of 3-6 carbon atoms, an alkyne of 3-6 carbon
atoms, and
Ar is an aromatic carbocycle represented by

7

wherein,
X is OR4, NR4R5, N02, SR4, SOOR4, SOONR4R5, Br, CI, F, or I,
M is-CHorN,and
Zis-CH,-NH,OorS
and wherein,
R3 and R4 are as described hereinbefore, and
R5 is H, or same as R4, and
R.2 is selected from the groups shown below, and the corressponding N-oxides thereof

Heteroaryl or Heterocycloalkyl wherein K is O, S, SO, S02, or CH2
According to another aspect of the invention there is provided a pharmaceutical
composition comprising:
i) atleast one of an antimycobacterially effective amounts of compound of formula I and
pharmaceutically acceptable salts there of; and ii) a pharmaceutically acceptable carrier.
According to yet another aspect of the present invention there is provided a method of inhibiting growth of mycobacterial cells such as Mycobacterium tuberculosis, drug resistant Mycobacterium tuberculosis, Mycobacterium avium-intracellular complex, M. fortuitum and M.kansai.,comprising administering an antimycobacterially effective amount of the compound of formula I and/or pharmaceutically acceptable salts thereof.
8

According to yet another aspect of the present invention there is provided a method of treating mycobacterial conditions such as Mycobacterium tuberculosis, drug resistant Mycobacterium tuberculosis, Mycobacterium avium-intracellular complex, M. fortuitum and M kansai, comprising administering an antimycobacterially effective amount of the compound of formula I and/or pharmaceutically acceptable salts thereof.
According to another aspect, there is provided a process for the manufacture of the compound of formula I or its pharmaceutically acceptable salts comprising : coupling the amino fragments of compound of formula II with the carboxylic acid fragment of formula III.
The above disclosed compound of formula I its pharmaceutically acceptable salts thereof are found to have antimycobacterial properties and the same in admixture with pharmaceutically active additives, an be administrated orally or paranterally for treatement of mycobacterial conditions especially TB. DETAILED DESCRIPTION OF THE INVENTION
In the pharmaceutically active compound of formula (I) of this invention,

the definition of the symbols and groups A, B, Rt and R2 are as follows :
A is either hydrogen or fluorine,
B is either hydrogen or fluorine,
A and B together is hydrogen and fluorine,
When A is hydrogen, B is fluorine and vice-versa.
R1 represents a group of formula,

Q is either an alkyl group of two carbon atoms (CH2-CH2), an alkene group of two to carbon atoms (CH=CH), or an alkyne group of two carbon atoms (C=C)
9

Y can either be oxygen, sulfur or an amino function of formula NR3, wherein
R3 is an alkyl group of 1-4 carbon atoms, both saturated and unsaturated, which can be straight or
branched. Suitable alkyl groups are methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl, tert-
butyl, ethylene, propylene, 1, butene, both the geometric isomers of 2-butene i. e.(cis)-2-butene
and (trans)-2-butene, and iso-butylene. or
R3 is a cycloalkyl group of 3-7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl, or
R3 is a carboxylic acid group (-COOH) or a carboxylic acid ester of formula-COOR4, wherein
R4 is H, an alkyl group of 1-4 carbon atoms, an alkene of 3-6 carbon atoms, an alkyne of 3-6
carbon atoms.
R3 is further an aldehyde (-CHO), an acetyl group (-COCR4), wherein R4 is as mentioned
hereinbefore or R3 is a nitrile (CN), aryl or heteroaryl, wherein
Aryl is phenyl substituted with (0) or (1) of-F, -CI, -OCH3, -OH, -NH2, -CrC4 alkyl, -O-C(O)-
OCH3,-N02or-CN,and
Heteroaryl
or Ar is a five membered ring of formula
or Ar is a fused bicyclic phenyl or pyridine ring of formula
10
The group Ar is a substituted phenyl ring or a substituted pyridine ring of formula

wherein,
M is either CH or N; Z is -CH, -NH, O or S and R3 is as defined hereinbefore,
X is a group selected from OR4, NR4R5, N02, SR4, SOOR4, SOONR4R5, F, CI, Br or I, wherein
R4 is as defined hereinbefore, and
R5 is hydrogen or R4.
R2 is selected from the groups shown below, and the corresponding N-oxides thereof.

78. (S) - N -[ [ 3 - ( 3 - fluoro - 4 - thiomorpholinylphenyl ) - 2 — oxo - 5 - oxazolidinyl ] methyl ] - 4 - ( 2,4 - dimethyl- 4 ethylphenyl) - 4 - oxobutanamide.
The respective N-oxides of the group R2 of the compounds of formula I listed above also form a novel aspect of the present invention.
The pharmaceutically active compounds of formula (I), the corresponding N-oxides of the group R2 and pharmaceutically acceptable salts thereof of this invention can be prepared by methods known to one skilled in the art.
Typically, compounds of formula (I), can be prepared by coupling of the amino fragment of formula (II)

Scheme-!
General method for synthesis of compounds of formula (I)

In a typical experiment, the amine compound of formula (II), wherein the groups A, B, and R2 have the same meanings as defined hereinbefore is dissolved in a 1:1 mixture of tertahydrofuran and water or a 1:1 mixture of methylene chloride and water. To the solution is added the carboxylic acid compound of formula (III), followed by addition of 1-hydroxybenztriazole (HOBt). The resulting mixture is cooled to a temperature of 0-5° C to which l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.1 Eq.) is added and gradually allowed to warm to room temperature and agitated at this temperature for 24 hours. At the end of
17

In a typical method, morpholine, thiomorpholine, piperidine, 4-benzyl piperazine, pyrrolidine, 1,2,4-triazine, 12,3-benzotriazine, benzyl amine, a heterocycloalkyl or a heteroaryl moiety etc., each one of which corresponds to the group R2 defined hereinbefore is reacted with 3,4-difluoro nitrobenzene in the presence of a base and a solvent to give the corresponding derivative in which the fluorine atom at 4-position is substituted by the group R2. The nitro group in the compound thus obtained is reduced to amino group, which is thereafter protected by a suitable protective group. Reaction of the N-protected compound thus obtained with (R)-glycidyl butyrate in the presence of a strong base like n-butyl lithium leads to formation of the 5-hydroxymethyl oxazolidinone ring. The hydroxy group in the compound thus obtained is converted to sulfonyl derivative, for e.g. a methanesulfonyloxy (mesyl) or a p-toluenesulfonyloxy (tosyl) derivative by reaction with methanesulfonyl chloride or p-toluenesulfonyl chloride respectively. Reaction of the respective mesyl or tosyl derivative with sodium azide gives the corresponding azide, which is converted to the amine compound of formula (II) by standard methods, for e.g. by reaction with a triaryl/trialkyl phosphine, followed by hydrolysis.
The starting carboxylic acid fragments of formula (III), wherein the group Ar has the same meaning as defined hereinearlier are prepared as per the method disclosed in Org. Reactions, 1949, 5, 229-289; Quart. Rev. Chem. Soc, 1954, 8, 355-379; Chem. Rev., 1955, 55, 229-281, and J. Am. Chem. Soc, 1947, 69, 1784-1786. The method is essentially summarized in Scheme-HI.
Scheme-Ill General method for synthesis ofalkane and alkene carboxylic acid s of formula (HI)

In a typical method, the aromatic compound Ar-H, wherein Ar is as defined hereinbefore is reacted with succinic anhydride in the presence of a Lewis acid, such as anhydrous aluminium chloride and in the presence of an anhydrous solvent and the mixture heated to 100° C to give the carboxylic acid derivatives of formula (HI), wherein Q is alkyl of 1-4 carbon atoms.
23

Similarly, compounds of formula (III), wherein Q is an alkene (CH=CH) are prepared by reaction of the aromatic compound Ar-H, wherein Ar is as defined hereinbefore with maleic anhydride under the same conditions mentioned hereinbefore.
Compounds of formula (III), wherein Q is an alkyne (C=C) are prepared by reaction of propiolic acid ester with an aldehyde of formula Ar-CHO in the presence of butyl lithium and in the presence of an aprotic solvent such as THF at -78° C to give the corresponding secondary alcohol, which is oxidized to the keto derivative using manganese dioxide as the oxidizing agent. Saponification gives the carboxylic acid derivative of formula (ID) [ US 4,929,741 (A. Fischili et. al.) ] The synthesis is summarized in Scheme-IV.

against M. tuberculosis including sensitive and resistant strains are summarized in Table-I. The MIC value of a representative preferred Compound No. 30 of formula I against different species of mycobacteria is summarized in Table-II. in vitro Growth Inhibition assay
The ability of the compounds 1-78 of formula (I) of this invention to inhibit the growth of Mycobacterium species was determined by the BACTEC 460 TB system. The reference strain M tuberculosis H37Rv ATCC 27294 was grown in Middlebrook 7H9 broth containing 10% ADC
supplement at 37°C on a rotay shaker at 150 rpm for grown for 7days. The turbidity of the culture was adjusted to 1.0 Mc farland. The BACTEC 7H12B medium vials were seeded with 0.1ml of the 1.0 Mc farland adjusted M. tuberculosis culture. In the control vials 0.1ml of the culture was added after lOOfold dilution of the initial inoculum. Stock solution of lmg/ml of each compound was prepared in DMSO in separate sterile tubes. The compounds were further diluted to concentration of 25 ^g/100 ul, 0.1ml was than added to the 7H12B vial containing mycobacterial culture so that final concentration of the compound 6.25 u.g/ml. The cap in all the vials were cleaned with isopropanyl alcohol and kept in racks. The vials were then incubated at 37°C without shaking. Test vials was read daily on the BACTEC system till the GI of the control vial reached > 30.Once the GI in the control reached 30 AGI (GI = GI (n> - GI („.i) ) was determined for all test and control vials. If AGI of test vial is less than that of the control vial the culture was sensitive to the test compound. in vitro Agar Dilution assay
MIC of compound of formula (I) of this invention against strains of Mycobacterium were determined by a reference agar dilution method as per the NCCLS- M24-T2. recommendations. The compounds were dissolved in DMSO and diluted twofold to obtain ten serial dilutions of each compound. Appropriate volume of compounds were incorporated into duplicate plates of Middlebrook7H10 agar medium supplemented with 10% Middlebrook supplement oleic acid-albumin-dextrose (OADC) enrichment at concentration of 0.03u,g/ml to 16|j,g/ml. Test organisms (mycobacterium strains) were grown in Middle brook 7H9 broth containing 0.05% Tween-80 and 10% ADC supplement. After 7 days of incubation at 37°C the broths were adjusted to the turbidity of 1.0 McFarland standard; the organism were further diluted 10 fold in sterile water containing 0.10% Tween-80. The resulting mycobacterial suspensions were spotted (3-5jxl/spot) onto drug supplemented 7H10 media plates. The plates were sealed and incubated at 37°Cfor 3-4 weeks in upright position. The MIC was recorded as the lowest dilution of the drug that completely inhibited the growth of test organisms. Test isolates included 10 clinical isolates that were generally susceptible to common tubercular agents and 10 strains that were resistant to one or more standard anti tubercular drugs. Appropriate reference strains and control drug was included in each batch of test.
42

in vivo studies:
The efficacy of the compound of formula (I) of this invention was also evaluated in murine model of pulmonary tuberculosis. Mycobacterium tuberculosis cultures grown in Middle brook 7H9 broth containing 0.05% Tween-80 and 10% ADC supplement at 37°C for 7 days on a rotary shaker. For, animal inoculation liquid cultures were declumped by brief sonication and were diluted appropriately in 7H9 broth to obtain a concentration of lxl07CFU's/ 0.2ml. Four-week-old male outbred Swiss albino mice housed in a pathogen free, biosafety level 3 environment within micro isolator cages were used throughout the study. Infections were produced by intravenous inoculation into caudal tail vein of 0.2ml of declumped M. tuberculosis suspension. Following infection, mice were randomly distributed in different groups of six each.
Treatment for initial study was started one day after infection. For, treatment Compound No. 30 of formula I was dissolved in 10% PEG. Isoniazid was dissolved in sterile water. The drugs were prepared each morning prior to administration. Therapy was given 5 days per week for four weeks. All the agents were administered by gavage and were dosed at 50,25,12.5mg / kg of body weight. Control group of infected but untreated mice were killed at the initiation of therapy (early control) or at the end of the treatment period (late control). Mice were sacrificed by cervical dislocation 3-5 days after the administration of the last dose of drug. The spleens and right lung were removed aseptically and homogenized in tissue homogeniser. At least 4 serial tenfold dilution of the homogenate was plated onto selective Middlebrook 7H11 agar plates in duplicate. The colony counts were recorded after incubation at 37°C for 4 weeks. The viable cell counts were converted to Logio values. A compound showing 2 Log reduction in viable counts compared to the controls was considered significant.
The in vivo data for a representative compound of formula (I) is given in Table-II.
Acute toxicity of Compound No. 30 of Chart-I was estimated in mice and the LDo was found to be >1000 mg/kg P. O.
43

Lung Spleen Lung Spleen
1 Compound 30 of Chart-I
50mg/kg 25mg/kg 12.5mg/kg 2.12 2.21 4.34 2.09 2.13 4.30 2.40 2.30 0.20 2.53 2.49 0.26
2 Isoniazid
50mg/kg 25mg/kg 12.5mg/kg 2.03 2.11 2.95 1.92 2.11 2.94 2.49 2.41 1.57 2.70 2.51 1.68
3 Infected early control 4.52 4.62
4 Infected late control 6.57 6.37
a- inoculation of logio:- 7.00 Mycobacteria.
b- mice were dosed 5 day/week for 4 weeks. From day 1 -28.
c- difference in mean logio number CFU from that of early controls.
The compound of formula I of this invention may be administrated to a subject such as a human being or an animal in need of such an administration through any route appropriate to the condition to be treatede. Suitable routes of administration include oral, rectal, nasal, topical (both buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intradermal, intrathecal and epidural).
Pharmaceutical compositions of compound of formula I can be prepared in adjunction with inert pharmaceutically acceptable carriers, which can either be solid or liquid.
Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories and ointments. The solid carriers can be one or more substances which may act also as diluents, flavouring agents, solubilisers, lubricants, suspending agents, binders or tablet disintegrating agents. It can also be finely divided solid which is in admixture with finely divided active compound. Suitable solid carriers are lactose, pectin, dicalcium phosphate, microcrystalline cellulose, sucrose, kaolin, dextrin, gelatin, starch, tragacanth, low melting wax, coca butter and the like.
Liquid preparations include solutions, suspensions and emulsions, e.g. solutions of compound of formula I in water or water-propylene glycol mixture for parenteral injection. Liquid preparations can also be formulated along with non-ionic surfactants and edible oils such as corn, peanut and sesame oils. Aqueous solutions for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours stabilizing and thickening
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agents, as required. Aqueous suspension for oral use can be made by dispersing the finely divided active component in water with a viscous material, e.g. natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose and othe known suspending agents. The adjuvants may also include preserving agents and anti-oxidants.
Compositions for topical application may take the form of liquids or gels, containing a therapeutically effective concentration of compound of formula I admixed with a dermatologically acceptable carrier.
The pharmaceutical preparations may be in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage can be in the form of tablets, capsules, powdersin vials or ampoules, ointments, gels, creams or any other form. The quantity or concentration of the active compound in such unit dose preparations may be varied or adjusted according to the particular application and potency of the active ingredient.
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A compound of formula (I) and its pharmaceutical^ acceptable salts

wherein,
A is either hydrogen or fluorine,
B is either hydrogen or fluorine,
A and B together is hydrogen and fluorine,
Ri is a group of formula,

wherein,
Q is either an alkyl group of two carbon atoms, an alkene group of two carbon atoms or
an alkyne group of two carbon atoms
Y is oxygen, sulfur or an amino function of formula NR3
wherein,
R3 is an alkyl group of 1-4 carbon atoms, both saturated and unsaturated, which can be
straight or branched; cycloalkyl of 3-7 carbon atoms; CHO, -COOH, -COOR,; COCR,;
CN; aryl or heteroaryl
wherein,
Rt is an alkyl group of 1-4 carbon atoms, an alkene of 3-6 carbon atoms, an alkyne of
3-6 carbon atoms.
Ar is a substituted phenyl ring or a substituted pyridine ring of formula

—O-R3
or Ar is a five membered ring of formula
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or Ar is a fused bicyclic phenyl or pyridine ring of formula

wherein,
M is either CH or N
Z is CH, NH, O, or S,
X is a group selected from OR,, NR4R5, N02, SR,, SOOR,, SOONR4R5, F, CI, Br or I,
wherein R4 is as defined hereinbefore, and
and R3 is as defined hereinbefore
R5 is hydrogen or R4
R2 is selected from the groups shown below, and the corresponding N-oxides thereof.

A compound according to Claim 1 wherein in said compound of formula I Aryl is phenyl substituted with (0) or (1) of F, CI, "OCH3, "OH, "NH2, CrC4 alkyl, 0-C(0)-OCH3," N02or"CN.
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